The United States has fallen, overthrown by a theocratic regime, founded on rigid Christian principles and the disempowerment of women, which has installed a new nation called Gilead in its place. The novel begins with Offred, the first-person narrator, remembering her restricted life at the Rachel and Leah Center, a training camp for Handmaids in an old high school. The scene changes to her current residence, where she lives with a Commander and his wife, Serena Joy. Offred puts on a red uniform and goes on a shopping trip with Ofglen, and afterwards they stop by the Wall to look at the bodies of recently executed men.
In the evening, Offred lies in bed. She remembers her spunky friend Moira, her activist mother, and the loss of her daughter and her husband, Luke. She thinks about the previous Handmaid who left a Latin message scratched into the wall. She describes her trip to the doctor on the previous day. The doctor suggested that her Commander might be sterile and offers to have sex with her. Though her life depends on getting pregnant, Offred refused.
She takes a bath and thinks about her daughter and the hysterical Handmaid Janine. After her bath, she and the rest of the members of the household gather to listen to the Commander read the bible. Then the Commander, the Commander’s wife Serena Joy, and Offred perform the Ceremony: the Commander has impersonal sex with Offred while she lies between Serena Joy’s legs. Afterwards, Offred sneaks downstairs in a rebellious gesture and runs into Nick, who gives her a message from the Commander to meet the following night.
The next day, Offred and other Handmaids attend Janine’s birth. In the afternoon, Offred remembers how Moira managed to escape from the Rachel and Leah Center disguised as an Aunt. In the evening she sees the Commander, who surprisingly only wants to play Scrabble and get a chaste kiss. Afterwards she can’t stop laughing.
Months pass. Offred and the Commander meet often, and the Ceremony becomes more fraught for Offred now that she and the Commander know each other. Offred and Ofglen go shopping regularly, and Ofglen reveals that she’s part of a secret organized resistance. Offred recalls all the events that lead from the US government to the Republic of Gilead—a massacre of the President and Congress, a succession of restrictive measures imposed for “safety,” the removal of all power and possessions from women. One night the Commander explains the meaning of the previous Handmaid’s Latin, and Offred learns that the previous Handmaid hanged herself.
After a shopping trip one day, Serena Joy tells Offred to have sex with Nick in an effort to get pregnant, and Offred agrees. Offred and Ofglen attend a Prayvaganza, celebrating arranged marriages. Afterward, Serena Joy shows Offred a photo of her daughter. That night, the Commander gives Offred a skimpy outfit and makeup, and Nick drives them to a nightclub/hotel filled with prostitutes. Offred spots Moira across the room, and they meet in the bathroom. Moira reveals that she spent many months on the Underground Femaleroad before she was captured. Offred and the Commander get a room and have sex, and Offred has to fake arousal.
Shortly after returning home, Serena Joy leads Offred to Nick, and Offred doesn’t have to fake arousal this time. Time passes, and Offred sees Nick often. She becomes so obsessed with him that she doesn’t want to leave or help Ofglen with Resistance efforts. Offred and Ofglen attend a Women’s Salvaging, where three women are hanged. Afterwards there’s a Particicution, a frenzied group murder of a supposed rapist, who was actually a member of the Resistance. The following day, a new Handmaid comes for the shopping trip with Offred. She says that the old Ofglen committed suicide when the Eyes—the Gilead secret police—came to get her.
When Offred returns home after shopping, Serena Joy confronts her with the skimpy outfit and threatens to punish her. Offred goes to her room and sees the Eyes coming for her. Nick tells her that they’re secretly members of the Resistance, and she enters their van, unsure of her fate.
The novel ends with “Historical Notes” from a future academic conference about Gilead. Professor Pieixoto describes the discovery of Offred’s narrative on cassette tapes in Maine, suggesting that the Eyes that took her were part of the Resistance, as Nick claimed. It is revealed that researchers may have discovered who the Commander was, but no one knows what happened to Offred.