The Prince of Tides is the tale of the destruction wrought upon the lives of a family through denial, abuse and lies. The story begins with the earliest recollections of Tom Wingo about his mother's love of language and the beauty of the natural world around them. It has profound but different effects on each to the three children - Luke, the eldest, and the twins Tom and Savannah. The children also learn a love of nature from their father, Henry Wingo, a man of unrefined behavior and traditional southern male attitudes.

The children grow to resent both father and mother as they grow up in the Wingo household, but they never really cease to love them in their own ways. Only Lila feels that the family is deprived and struggles to rise above the lower class label she has lived under all her life. She tells fabulous lies about her ancestry to delude herself but is never really able to delude either her family or the citizens of Colleton.

Only Lila and the children know a deep family secret, and they have sworn never to reveal it. That secret is the detonator, though not the origin, of Savannah's lifelong struggle with insanity. Savannah tries to escape by moving to New York just as her grandmother, Tolitha, escaped her dull life years before. Tom settles into a life of mediocrity, not living up to the expectations everyone has always had of him.

Tom's marriage is falling apart when Lila comes to tell him of another psychotic episode Savannah is having in New York. Lila has married an archenemy, Reese Newbury, and put yet another strain on the family. Tom, now out of work, is dispatched to go and try to help Savannah. He stays for weeks in the city that Savannah has adopted, and he despises it for its coldness and unfamiliarity. There he meets Dr. Susan Lowenstein, Savannah's psychiatrist, and agrees to help her understand his sister so that she can try and bring Savannah out of the psychosis.

Over a period of time, Tom tells the family history to Dr. Lowenstein. During that process, two things happen to Tom. He coaches Lowenstein's son, Bernard, to become a football player, and he falls in love with the doctor. Tom knows Sallie, his wife, is having an affair in South Carolina, and it leaves him vulnerable to do the same with Susan Lowenstein.

The demolition and relocation of Colleton as well as the loss of Melrose Island, the long time family home, set about the ultimate chain of events that culminate in Tom and Savannah's problems. Tom's final telling of the family "secret" and the tragic death of Luke finally unlocks his own mental problems and Savannah's psychotic episode. The epilogue to the story presents a ray of hope for Tom, now reconciled with his own wife and children, and an uncertain future for the fragile Savannah.