The following version of this novel was used in the creation of this study guide: Woodruff, Samantha Greene. The Lobotomist’s Wife. Lake Union Publishing. 2022. Paperback.

The novel starts with a young mother named Margaret in 1952 who is struggling from deep, postpartum depression.

In 1933, a mid-thirties woman named Ruth Emeraldine works as an assistant superintendent at her father's hospital, Emeraldine Hospital, after her brother Harry committed suicide due to his post-war depression. Her love for her patients and desire to find progressive cures convinces her to hire a radical psychologist named Robert Apter. Eventually, the two fall in love and get married, with Ruth accompanying him on many neurology events and learning about new research into psychiatric care.

Around 1936, they hire a brain surgeon named Edward Wilkinson and decide to bring a new form of treatment - the lobotomy - to the States after the success of the similar leucotomy by Dr. Moniz. Their first patient is a woman named Penelope who suffers from extreme OCD and obsession after losing her family to an illness and being abused for much of her life. The surgery seems to be a success, as Penelope leaves happy and healthy for the first time in years. However, while Robert, Edward, and Ruth are all hopeful about the new treatment and perform it on many others, Ruth's father, Bernard, is furious that they would consider such a procedure and refuses to acknowledge Ruth or Robert's accomplishments to his death. Unfortunately, his concerns turn out to be right five years later when a failed lobotomy on Rosemary Kennedy led to her mental state regressing to that of a toddler. Still, Robert is hopeful that the lobotomy will become a miracle cure.

Meanwhile, in 1952, Margaret's depression is worsening and she struggles to take care of both the new baby and the rest of her family. Eventually, she breaks down in front of her husband and admits that she thinks something is really wrong with her, even though she is not sure what. They agree to see a doctor together.

Between the years of 1941 and 1947, Ruth takes over the hospital from Charles after her father's death as he, supposedly, wanted her to inherit it all along. As World War II leads to many traumatized veterans overcrowding hospitals and psychiatric facilities, Robert and Edward come up with the idea of a transorbital lobotomy. Essentially, it reduces the procedure down to a ten-minute, anesthetic free surgery that can be done anywhere but any doctor. However, Edward is furious when Robert performs the first iteration of this in his own office without any safety precautions and leaves the team when Robert refuses to acknowledge his wrongdoing. Despite this, the use of the transorbital lobotomy spreads and Robert begins performing surgeries from his car all around the country.

However, when an embezzlement scandal forces Ruth to focus more heavily on the administrative side of the hospital, she begins to see some inconsistencies with Robert's procedures and the patient's long-term care. By 1952 and after many months of research, Ruth is horrified to learn that most of Robert's patients are actually living worse lives after their procedures, with only 20% leaving the hospital at all. Furthermore, many of those that are seen as successes are struggling with bigger issues of obsession, madness, and moments of violence. Eventually, she learns of a man named Sam that Robert gave a lobotomy to without authorization or the man's permission, and Ruth decides she needs to stop Robert. Knowing that her own reputation will be ruined, Ruth reports Robert's malpractice and fights to get his license removed.

Meanwhile, Margaret begins visiting Robert who uses her feelings of insecurity and occasional anger to convince her that she is suffering from something much more extreme than postpartum depression. Ruth, however, disagrees, especially when Margaret begins to improve with the support of her husband and friendship with Ruth. However, Robert's insistence and Margaret's fear of slipping back into her depression convinces her that she needs to have the lobotomy.

The two women's stories collide when Ruth begs Margaret not to have the lobotomy and confronts Robert herself. He knocks Ruth unconscious during the argument, but she is able to come to in time to help Frank save Margaret from the procedure that Robert was about to force on her. Later, Ruth recognizes that Robert has done a lot of good in the world, but his obsession with the lobotomy and refusal to see that it was not meant for everyone destroyed those good intentions. With Edwards' help, she kicks Robert out and reports his story to the Times, ensuring that he cannot practice medicine ever again.

A year later, Ruth has converted her estate into an aftercare facility for those affected by the procedure and Robert's reputation is ruined. She thinks of her brother Harry, realizing that not every illness has a treatment. Sometimes, people just need compassion and understanding to heal over time.