Harry is at his stepparent's house for the summer and Uncle Vernon's dreadful sister, Marge comes for a visit. Harry also has a permission slip for Vernon to sign, and Vernon promises to sign it if Harry is good. But Marge angers Harry, because he thinks she is talking about his parents, when she is really talking about dogs, and when he gets angry, she suddenly starts blowing up like a balloon and flies out the window, flying over Surrey like a blimp. This angers Vernon, causing Harry to run to his room, pack his stuff and leave. He runs away and sit outside a park when he thinks he sees something. Then suddenly out of the blue, a towering violently purple 3 decker bus pulls up. The front of the bus says The Knight Bus on it. He gets on and it takes him on a wild ride through the streets of London at night, where he finally reaches his destination, the Leaky Cauldron. This is where he meets the Minister of Magic, Cornelius Fudge, who tells Harry he is not in any trouble for blowing up his aunt. Fudge also tells him about a person named Sirius Black, a madman prisoner who escaped from Azkaban and is intending to kill Harry. He also learns that while over the summer, Ron, Hermione had come to the Leaky Cauldron and are staying there too.
- Daniel Radcliffe as Harry Potter, the film's protagonist.
- Rupert Grint as Ron Weasley, one of Harry's best friends.
- Emma Watson as Hermione Granger, Harry's other best friend.
- Robbie Coltrane as Rubeus Hagrid, the Hogwarts gamekeeper and the new Care of Magical Creatures teacher.
- Michael Gambon as Albus Dumbledore, the Hogwarts Headmaster. Gambon assumed the role after Richard Harris, who played Dumbledore in the previous two films, died on 25 October 2002. Despite his illness, Harris was determined to film his part, telling a visiting David Heyman not to recast the role. Four months after Harris's death, Cuarón chose Gambon as his replacement. Gambon was unconcerned with bettering or copying Harris, instead giving his own interpretation, putting on a slight Irish accent for the role, as well as completing his scenes in three weeks. Rumours of Ian McKellen being offered the role started to spread, but when confronted, he turned the rumours down, stating that he has played a similar character named Gandalf in The Lord of the Rings trilogy. He also stated it would have been inappropriate to take Harris' role, as the late actor had called McKellen a "dreadful" actor. Harris's family had expressed an interest in seeing Harris's close friend Peter O'Toole being chosen as his replacement.
- Richard Griffiths as Vernon Dursley, Harry's Muggle uncle.
- Gary Oldman as Sirius Black, an escapee from the Wizarding prison Azkaban and Harry's godfather. Oldman accepted the part because he needed the money, as he had not taken on any major work in several years as he had decided to spend more time with his children. He drew inspiration from Cuarón, who he described as having "such enthusiasm and a joy for life," and compared Sirius to John Lennon. He was "surprised by how difficult it was to pull off", comparing the role to Shakespearean dialogue. Oldman suggested Sirius's hairstyle, while Cuarón designed his tattoos. He had read the first book, and his children were fans of the series. The part made Oldman a hero with his children and their schoolmates.
- Alan Rickman as Severus Snape, the Potions master at Hogwarts.
- Fiona Shaw as Petunia Dursley, Harry's Muggle aunt.
- Maggie Smith as Minerva McGonagall, the Transfiguration teacher at Hogwarts.
- Timothy Spall as Peter Pettigrew, a friend of Harry's parents said to have been killed by Sirius Black.
- David Thewlis as Remus Lupin, the new Defence Against the Dark Arts teacher at Hogwarts. Thewlis, who had previously auditioned for the role of Professor Quirrell in Harry Potter and the Philosopher's Stone, was Cuarón's first choice for the role of Lupin. He accepted the role on advice from Ian Hart, the man who was cast as Quirrell, who told him that Lupin was "the best part in the book." Cuarón told Thewlis that he thought Lupin was gay, pitching him as a "gay junkie", although his idea turned out to be incorrect. Thewlis had seen the first two films and had only read part of the first book, although after taking the role he read the third. He was excited about the prospect of making a children's film, and thoroughly enjoyed filming.
- Emma Thompson as Sybill Trelawney, the inept Divination teacher at Hogwarts.
- Julie Walters as Molly Weasley, the Weasley matriarch and a mother figure to Harry.