Natalie Cook (Diaz), Dylan Sanders (Barrymore), and Alex Munday (Liu) are the "Angels," three talented, tough, attractive women who work as private investigators for an unseen millionaire named Charlie (voiced by Forsythe). Charlie uses a speaker in his offices to communicate with the Angels, and his assistant Bosley (Bill Murray) works with them directly when needed.
The Angels are assigned to find Eric Knox (Sam Rockwell), a software genius who created a revolutionary voice-recognition system and heads his own company, Knox Enterprises. Knox is believed to have been kidnapped by Roger Corwin (Tim Curry), who runs a communications-satellite company called Redstar. The Angels infiltrate a party held by Corwin and spot a thin man (Crispin Glover) who was seen on the surveillance videos during Knox's kidnapping. They chase and fight the thin man, but he runs away. When they follow him, they discover Knox.
After the Angels reunite Knox with his business partner Vivian Wood (Kelly Lynch), Charlie explains that they must determine whether the thin man has stolen Knox's voice-recognition software. The Angels infiltrate Redstar headquarters, fool the security system, and plant a device in the central computer that will enable them to explore it remotely. They retire for the night after giving Bosley the laptop computer that communicates with the Redstar computer. Dylan takes up Knox's offer to spend the night with him, but he betrays her later that night, explaining that he faked the kidnapping with help from Vivian and the thin man. He has kidnapped Bosley, and, with access to Redstar's central computer, he intends to use his voice software with the Redstar satellite network to find and kill Charlie, who he believes killed his father in the Vietnam War.
Knox shoots at Dylan, apparently killing her, but she escapes unharmed. Natalie and Alex are also attacked, and Corwin is murdered by the thin man. When the Angels regroup, Charlie's offices are blown up, but a radio receiver survives in the rubble, and the Angels deduce Bosley's location as he speaks to them using a radio transmitter implanted in his teeth.
With help from Dylan's current boyfriend Chad (Tom Green), the Angels approach the abandoned lighthouse where Knox is holding Bosley prisoner. The Angels rescue Bosley and defeat Vivian, the thin man, and some henchmen before Knox blows up the lighthouse, but Knox uses his software and the Redstar satellite network to locate Charlie when he telephones Bosley. When Knox escapes in a helicopter armed with a missile, Bosley helps the Angels board the helicopter, and Alex reprograms the missile, which blows up the helicopter and kills Knox while the Angels land safely in the ocean. Seeing the opportunity to finally meet Charlie in person, the Angels enter the beach house that Knox targeted, but Charlie has already left. He remotely congratulates them on a job well done, and treats them and Bosley to a vacation. When Charlie speaks to the Angels by telephone on the beach, unseen by most of the group, Dylan suspects that she sees him nearby talking into a cell phone.