In San Francisco in 1941, private investigators Sam Spade (Humphrey Bogart) and Miles Archer (Jerome Cowan) meet prospective client Ruth Wonderly (Mary Astor). She claims to be looking for her missing sister, who is involved with a man named Floyd Thursby. Archer agrees to follow her that night and help get her sister back.
Spade is awakened by a phone call early in the morning and the police inform him that Archer has been killed. He meets his friend, Police Detective Tom Polhaus (Ward Bond), at the murder scene and then tries calling his client at her hotel, but she has checked out. Back at his apartment, he is grilled by Polhaus and Lieutenant Dundy (Barton MacLane), who tell him that Thursby was also murdered the same evening. Dundy suggests that Spade had the opportunity and motive to kill Thursby, who likely killed Archer. Archer's widow Iva (Gladys George) later visits him in his office, believing that Spade shot his partner so he could have her.
Later that morning, Spade meets his client, now calling herself Brigid O'Shaughnessy. She explains that Thursby was her partner and probably killed Archer, but claims to have no idea who killed Thursby. Spade distrusts her, but agrees to investigate the murders.