Brian Cohen is born in a stable next door to the one in which Jesus is born, which initially confuses the three wise men who come to praise the future King of the Jews. Brian later grows up into an idealistic young man who resents the continuing Roman occupation of Judea. While listening to Jesus's Sermon on the Mount, Brian becomes infatuated with an attractive young rebel, Judith. His desire for her and hatred of the Romans, further exaggerated by his mother revealing Brian himself is half-Roman, inspire him to join the "People's Front of Judea" (PFJ), one of many fractious and bickering independence movements which spend more time fighting each other than the Romans.
Brian participates in an abortive attempt by the PFJ to kidnap the wife of Roman governor Pontius Pilate but is captured by the palace guards. Escaping when the guards suffer paroxysms of laughter over Pilate's speech impediment, Brian winds up trying to blend in among prophets preaching in a busy plaza, repeating fragments of Jesus' sermons. He stops his sermon mid-sentence when some Roman soldiers depart, leaving his small but intrigued audience demanding to know more. Brian grows frantic when people start following him and declare him to be the messiah. After spending a night in bed with Judith, Brian discovers an enormous crowd assembled outside his mother's house. Her attempts at dispersing the crowd are rebuffed, so she consents to Brian addressing them. He urges them to think for themselves, but they parrot his words as doctrine.
The PFJ seeks to exploit Brian's celebrity status by having him minister to a thronging crowd of followers demanding miracle cures. Brian sneaks out the back, only to be captured by the Romans and is sentenced to crucifixion. En route to crucifixion, the real Jesus escapes by switching places with a Weedy Samaritan offering to help carry his cross. In celebration of Passover, a crowd has assembled outside the palace of Pilate, who offers to pardon a prisoner of their choice. The crowd shouts out names containing the letter "r", mocking Pilate's rhotacistic speech impediment. Eventually, Judith appears in the crowd and calls for the release of Brian, which the crowd echoes, and Pilate agrees to "welease Bwian".
His order is eventually relayed to the guards, but in a scene that parodies the climax of the film Spartacus, various crucified people all claim to be "Brian" so they can be free and the wrong man is released. Other opportunities for a reprieve for Brian are denied as the PFJ and then Judith praise his martyrdom, while his mother expresses regret for having raised him. Hope is renewed when a crack suicide squad from the "Judean People's Front" charges and prompts the Roman soldiers to flee; however, the squad commits mass suicide as a form of political protest. Condemned to a slow and painful death, Brian finds his spirits lifted by his fellow sufferers, who cheerfully sing "Always Look on the Bright Side of Life."
Graham Chapman as Brian Cohen (of Nazareth), Biggus Dickus (who has a lisp), 2nd wise man
John Cleese as Reg, High priest, Centurion of the Yard, Deadly Dirk, Arthur, 1st wise man
Terry Gilliam as Another person further forward (at Mount – "Do you hear that? 'Blessed are the Greek'!"), Blood and Thunder prophet, Geoffrey, Gaoler, Frank
Eric Idle as Mr. Cheeky, Stan/Loretta, Harry the Haggler, Culprit woman who casts first stone, Intensely dull youth, Otto, Gaoler's assistant, Mr. Frisbee III
Terry Jones as Mandy Cohen (Brian's mother), Colin, Simon the Holy Man, Bob Hoskins, Saintly passer-by
Michael Palin as Mr. Big-Nose, Francis, Mrs. A, Culprit woman who casts second stone, Ex-leper, Ben, Pontius Pilate, Boring Prophet, Eddie, Nisus Wettus, 3rd wise man
Terence Bayler as Mr. Gregory, 2nd Centurion
Carol Cleveland as Mrs. Gregory, Elsie
Charles McKeown as False Prophet, Blind Man, Giggling Guard, Stig
Kenneth Colley as Jesus
Neil Innes as A Weedy Samaritan
John Young as Matthias
Gwen Taylor as Mrs. Big-Nose, Woman with ill donkey, Female heckler
Sue Jones-Davies as Judith Iscariot
Chris Langham as Alfonso, Giggling Guard
Andrew MacLachlan as Another Official Stoners Helper, Giggling Guard
Bernard McKenna as Parvus, Official Stoners Helper, Giggling Guard
Randy Feelgood as Man, Woman
George Harrison as Mr. Papadopoulis
Charles Knode as Passer-by (uncredited)
Several characters remained unnamed during the film but do have names that are used in the soundtrack album track listing and elsewhere. There is no mention in the film that Eric Idle's ever-cheerful joker is called "Mr. Cheeky", or that the Roman guard played by Michael Palin is named "Nisus Wettus".
Spike Milligan plays a prophet, ignored because his acolytes are chasing after Brian.