The story centers around a day in the life of an Indian tour guide, Mr. Kapasi. An Indian-American family has come to India on vacation, obtaining his services as their guide. There are five in the family: Mr. and Mrs. Das, along with their children Ronny, Bobby and Tina. Mr. Kapasi is quickly struck with how "American" they are in dress, language and actions.
During their discussions on the road, Mrs. Das becomes extremely interested in Mr. Kapasi's other job as an interpreter for a physician. She is so interested that Mr. Kapasi begins to fantasize about a relationship between Mrs. Das and himself. This occupies his mind for a great part of the story.
But when they make a detour and stop to visit an old abandoned monastery things change. When Mr. Das and the children get out to take pictures of some monkeys, Mrs. Das stays with Mr. Kapasi. She moves to the front of the car to sit with him and begins to tell him the story of how their middle child, Bobby, is not her husband's son, but the son of one of his friends. After a long confession, she asks his opinion since she sees him as an "Interpreter of Maladies." When she doesn't like his answer, she gets mad and leaves the car to join her family.
Mr. Kapasi rescues Bobby from some of the monkeys that have gotten a bit too aggressive and his fantasies about Mrs. Das drift away on the wind with a note on which she had gotten him to write his address.