"Calling Me Home" tells two stories, that of Isabelle McAllister and of Dorrie Curtis. Isabelle, a 90-year-old white woman from Kentucky, asks Dorrie, a 40-something black woman from Texas, to bring her from where they live, Arlington, Texas, up to Cincinnati, Ohio. Dorrie calls Isabelle Miss Isabelle, but she is mostly referred to as Isabelle by the other people in her life. Isabelle asks on short notice, but Dorrie, feeling honored and intrigued at the request, rearranges her salon appointments and agrees to take Isabelle about a thousand miles Northeast. Dorrie leaves her two children with her elderly mother, and the two start out on their journey in Isabelle's vehicle.

During their road trip, Isabelle tells Dorrie the story of her life when she was just 17 years old. At the time, Isabelle was living with her parents and two brothers in Shalerville, Kentucky, a small town just a little across the Ohio river from Cincinnati. Isabelle is in quiet rebellion of the life her parents lead, and therefore lands in a potentially dangerous situation with a man she meets at a nightclub she sneaks out to. Robert, a young black man who is also the son and brother of Isabelle's housemaids, Cora and Nell, interferes with the situation and saves Isabelle from harm.

Robert walks Isabelle home, but must do so very carefully and while walking a few paces behind her, since black people aren't allowed in Shalerville after sundown. Isabelle is grateful for his protection, but is also intrigued by him. The two are tutored together by Isabelle's father, as she completes her regular schoolwork and he is working toward being a medic in the Army. She begins to find every excuse she can to see and/or talk to Robert.

In the meantime, Dorrie is trying to figure out if she should trust the man she just started dating, Teague. He proves his truth worthiness by calling when he says he'll call, texting her to see if she's doing okay, and helping her with a theft situation at the salon she owns. As Dorrie listens to Isabelle's story, she wonders if she can trust Teague since her own father wasn't present and her ex-husband is lazy and untrustworthy. Isabelle coaches Dorrie on what makes a good man.

Dorrie is also dealing with her 17-year-old son, Stevie Junior. He tells her that Bailey, his girlfriend, is pregnant, and that he is the one who stole the cash from the filing cabinet at her salon. Dorrie is beyond embarrassed that Teague is helping her with the theft, and it was her own son who did the stealing. She avoids Teague's calls and text messages.

Cora, Nell, and Isabelle's mother pick up on Isabelle's feelings for Robert. Cora and Nell discreetly try to ward off any interactions between Isabelle and Robert, while Isabelle's mother tells Isabelle to be less friendly with the Prewitt family, as they need to know their place and she, hers. Yet, Isabelle manages to follow Robert out of town and out to an arbor where he works to clear the debris for his home church. Isabelle begins going to the arbor every Wednesday under the guise of going to the library.

At this point in Isabelle's story, she and Dorrie have come to Memphis, Tennessee, for their first stop on their two-day road trip. They experience a slight instance of racism by the hotel clerk, but Isabelle isn't afraid to tell him what's on her mind. Outside of Memphis the next day, Dorrie stops at a university at Isabelle's request. It is the university where Robert went to school, and where his name is engraved on a War memorial.

Isabelle describes how she and Robert developed a strong courtship over the course of a year. They share a kiss after being caught in a rainstorm, and Robert calls Isabelle, Isa, after she tells him not to call her Miss Isabelle because it's too formal. Robert is uncomfortable with that at first, since blacks must refer to whites with respect, but eventually comes to calling her by the nickname he's chosen for her.

Isabelle and Robert share conversations about their hopes for the future. They work very hard - Robert more than Isabelle - to not discuss their feelings for one another, since interracial relationships were highly frowned upon in 1939. Eventually, though, Isabelle tells Robert that she might love him. Robert resists a relationship with Isabelle for a long time, saying it's too risky, since interracial relationships are considered a grave offense. Isabelle feels put off, and the two don't see each other for two weeks.

Nell approaches Isabelle and tells her that ever since an interaction she saw of Isabelle and Robert's, the two of them have been moping around their respective homes and Nell can't take it anymore. She offers to be a carrier for letters back and forth between Isabelle and Robert.

As the two write letters, Isabelle's have more emotion from the start. Robert's letters are full of rote facts that give nothing away as to how he feels, until the late fall when he refers to Isabelle as "you"; before that letter, he had never specifically referenced Isabelle. On Robert's breaks from school the two see each other at the arbor. Isabelle wants to marry, but Robert says they can never marry. He remains afraid of the social consequences should their relationship ever become public. Plus, he tells her, it's illegal.

Isabelle so wants to marry Robert that she goes to the Hamilton County Courthouse in Cincinnati, Ohio, across the river from where she lives, to see if interracial marriage is legal in Ohio. It is legal, and she lets Robert know.

Isabelle and Robert continue writing letters, and in a letter that same winter, Robert proposes marriage to Isabelle. He works hard to secure a job in Cincinnati, as well as a place for them to live. Isabelle reveals their plans to Nell for two reasons: she is bursting to tell someone, and she needs help. Nell helps Isabelle press her best dress, and get together a small bag of things Isabelle will need. She is planning to leave home for good to marry Robert, so she needs help gathering the right supplies.

In January 1940, Robert and Isabelle meet outside of Shalerville and go across the river to Cincinnati. The two get their marriage license on a Monday. The following Saturday, Isabelle leaves home to marry Robert. The two marry in a ceremony that is just the two them aside from Reverend Day and his wife, Sarah; they give Isabelle and Robert a thimble to act as a wedding ring. The thimble has the phrase, "FAITH. HOPE. LOVE." printed on the side. Isabelle and Robert stay in a room at a rooming house for their first home, timidly practicing marital intimacy.

The next day, Robert is out getting breakfast when Isabelle's brothers and father burst into her room. They are furious with her and with Robert, and force Isabelle to return home without Robert. Her family tells her the marriage is annulled since Isabelle is only 17 years old and lied to obtain the certificate. Isabelle is kept under a tight watch.

Mrs. McAllister fires Cora and Nell as soon as Isabelle's pregnant stomach starts showing; Mrs. Gray becomes the McAllister's housekeeper. As Isabelle is stuck inside with her condition of being pregnant, she is miserable. She is followed to and from the bathroom, and anywhere else in the house she wants to go. When she and her mother eventually have an argument, Isabelle gets so worked up that she doesn't watch her step and ends up falling down the stairs.

As Dorrie listens to Isabelle's story, she contemplates her own history as she grieves for Isabelle's losses. She wonders if she should change things in her life while she still can, before it's too late and she loses people she cares about.

Dorrie is pulled over for speeding just as her son is telling her what a terrible mother she is, one who never properly showed him love, which he claims is why he's acted out by having sex with his girlfriend. Dorrie gives the phone to Isabelle so she can concentrate on pulling to the side of the road. Isabelle promptly tells Stevie Junior to think about what he's saying and to call back when he's calmed down. Dorrie doesn't receive a speeding ticket, but she's sure that's just because she is sitting next to Isabelle, who is white.

Dorrie's car breaks down just thirty miles after getting pulled over. Teague calls her and she accidentally answers, so she gets off the phone with him as soon as she can, as she's not yet ready to decide if she's going to trust him or not. She's also still embarrassed about her son being the thief.

Back to Isabelle's story, falling down the stairs causes Isabelle's baby to be born prematurely. Her mother and the midwife make it appear to Isabelle as though the infant has died. Isabelle becomes more despondent than ever. When she gets her strength back, her mother tells her that she's free to come and go as long as she does not admit that she's been in Shalerville during the time Mrs. McAllister told everyone she'd been away.

When her body recovers after the pregnancy, Isabelle visits Cincinnati. She goes to the rooming house where she and Robert spent their first night as a married couple. She sees Nell at the supermarket, which is an awkward interaction. Nell tells Isabelle that Robert is joining the Army to be a medic. In Cincinnati, Isabelle also secures a job and a place to live so that she can leave home once and for all. Isabelle needs $7 to secure the room she's found to stay in, a large sum especially since she doesn't have a job. She asks her father for the money, and he gives her $15. Their interaction is hesitant and awkward, due to him betraying their close relationship and letting Isabelle's brothers control his decision to force Isabelle away from Robert.

After some time of being alone, Isabelle is encouraged by a friend in Cincinnati to attend a public weekend dance in the community. She reluctantly agrees, but meets a man named Max, who asks her three times to dance with him before she says yes. Max is predictable, reliable, and persistent in his pursuit of Isabelle.

After a short courtship, Isabelle marries Max. She is complacent in the life she doesn't want to be living, but knows it's better than living one by herself. One afternoon while Isabelle is gardening, Robert visits her at her home while Max is at work. Robert tells her of her brothers' visit to Robert soon after the two were forced apart; Jack and Patrick almost killed Robert, which is why Robert didn't go looking for Isabelle. The two are intimate in Isabelle and Max's bed, and Robert promises to come back for her with a safe place she can stay until he's back from overseas, where he's going to serve for World War II.

Soon after Robert's visit, Isabelle realizes she's pregnant. However, she doesn't know whose child it is, since she was intimate with Max just the night before she was intimate with Robert. Isabelle decides that, for the safety of her child, she is going to stay with Max. She figures even if he is darker skinned, it'll be better to be raised by an all-white couple than an interracial one. Robert is upset with her decision, yet he still promises to come back. But he never does, which Dorrie learns when the two visit a memorial on his college campus with his name on it.

When Dorrie and Isabelle get to Cincinnati, they visit Robert's grave site after going to the bed and breakfast but before going to the funeral home. At the funeral home, Isabelle sees pictures of the person whose funeral it is and the reader learns that it's her daughter she thought had died back in 1940; her name was Pearl.

Isabelle and Nell reunite at the funeral home, showing no signs of anger toward each other as they embrace. It is after the funeral the following day that Nell fills Isabelle in on what happened surrounding Pearl's birth, as well as some bits and pieces about the Prewitt family since then. Isabelle listens to the entire story but shows little affect.

The night of the wake, Dorrie leaves a voicemail for Teague telling him she really likes him, she's sorry for how she's been acting, and she hopes they can work out a relationship. She's nervous as she leaves the message, but knows it's necessary.

When Isabelle and Dorrie arrive back in Arlington, it's a Saturday. Dorrie and Teague remain a couple, as she decides to trust him and he is patient with her as she tells him things going on in her life. Dorrie is happy that Teague waited for her while she traveled to and from Cincinnati, and that the two can continue dating. Dorrie also has a sit-down talk with Stevie Junior. Bailey miscarried the baby, and Dorrie and her son bond over the loss. Dorrie reminds him that he's still not yet a full-grown adult, and that she can help him make big decisions if he'll involve her.

Dorrie promises to be at Isabelle's house on the upcoming Monday to do her hair. However, the reader learns in the last chapter that Miss Isabelle passed within forty-eight hours of coming home from Cincinnati. She has her hands clasped at her waist, clutching the thimble given to her by Reverend Day and his wife, and Dorrie sets her hair one last time.