Dylan (DREW BARRYMORE), Natalie (CAMERON DIAZ) and Alex (LUCY LIU) are three beautiful and sexy private investigators who work for Charlie Townsend (voice of JOHN FORSYTHE), a reclusive figure they've never met and who delivers their assignments to them via speakerphone. Proficient in espionage through their use of various high-tech tools, martial arts and disguises, the "Angels" - along with Charlie's front man, Bosley (BILL MURRAY) - always get the job done.
Their latest assignment involves finding Eric Knox (SAM ROCKWELL), the founder of Knox Technologies who's just been kidnapped. He's recently designed a voice-identification program that's more accurate than fingerprinting and Vivian Wood (KELLY LYNCH), the president of his company, believes that rival Roger Corwin (TIM CURRY), who runs Red Star Systems, may be behind the crime.
As the Angels begin to investigate Corwin, have various violent encounters with a mysterious character known only as the Thin Man (CRISPIN GLOVER), and deal with various significant others in their lives such as Jason (MATT LeBLANC), Chad (TOM GREEN) and Pete (LUKE WILSON), they deploy all sorts of disguises and tools while trying to solve the crime. What they uncover, however, soon puts their, Bosley's and Charlie's lives in dangers.