The following version of the book was used to create this study guide: Arnold, David. Mosquitoland. Penguin Group, New York, New York, 2015. Kindle AZW file.

Mary Iris Malone, known to most as Mim, recently moved to Mississippi with her dad Barry and stepmom Kathy. Barry and Kathy drop the bomb that Mim is soon to have a little sister at a time when Mim is reeling over the lack of contact with her mother, Eve. When Mim overhears Kathy and Barry talking to a school official, she discovers that Eve is ill. Immediately, she sets out to make the trip from Mississippi to Ohio, believing that being with Eve will set everything right. She rushes home where she steals a coffee can of cash that Kathy has been saving. Mim then goes to the bus station and buys a ticket to Ashland, Ohio. She is expecting that her mother will be living in the same house.

Mim immediately judges the people she meets, including the bus driver Carl who does not seem to live up to the other "Carls" she has met. There is a creepy man wearing a poncho that makes Mim nervous. She ends up sitting beside an older woman named Arlene as they begin the trip. Arlene soon proves that she is not what Mim expected. She compliments Mim's shoes (the shoes Kathy hates) and says she is headed to Independence, Kentucky, to deliver a box to her nephew. She offers details about this nephew, and Mim finds herself wondering what could possibly be in the box.

The trip is cut short when the bus wrecks, tipping onto its side. Arlene is among the dead. Mim instinctively takes the box, though she is not certain why. Carl steps up, taking care of those who wish to continue their trip and driving the next leg of the journey, even though he was injured as well.

Mim has a brutal encounter with the man in the poncho who corners her in a ladies' bathroom. She knows that he is a predator, but she also knows that reporting him will cut her trip short. In Independence, Kentucky, Mim decides to leave the bus, partly because of the creepy man. The following day, she meets Beck, a college student who discovered the man in the poncho had molested another girl in another bathroom. Beck punched the man which led to a brief police inquiry and being banned from the bus. By that time, Mim has spent some time with Walt, a young man who has developmental issues and was about to be robbed by a young thief. While Walt and Mim are running from the thief, Mim encounters Arlene's nephew and hands over the box without ever knowing what was in it. The police briefly interview Walt and Mim as well, and the two slip away when police begin to talk about finding an adult to be responsible for them.

Mim and Walt try to buy a truck, and Beck steps in to help. Beck begins to reveal details about his life, including that he has dropped out of school. Mim tells him about herself, including her desire to find her mother and her hatred of Kathy, who perfectly fits the role of the evil stepmother. Mim finds herself feeling protective of Walt while falling in love with Beck. Beck feels similarly protective of Walt but says he is too old for Mim, but just “for now.”

When they reach the home Mim lived in with Eve and Barry, they find it abandoned. Kathy arrives, and her presence makes Mim face some truths, including that Kathy asked Eve to see Mim, but Eve refused. Mim discovers Eve is in a rehabilitation facility and that she is not happy to see Mim. Mim thinks back over events that brought her here. Barry has insisted she medicate in order to keep mental illness at bay, and Mim knows it is because he feels guilty that he did not save his sister who committed suicide. Mim realizes that Barry needs someone like Kathy as a balance to the years he spent with the high-strung Eve. She also realizes that she is looking forward to having a little sister, who will be named Isabel in honor of Barry's sister. After she spends a short time with Eve, Mim finds a note from Beck, pledging to take care of Walt and to meet Mim the following spring.