Executive Meddling: The original script had more Family-Unfriendly Violence and more nudity on the part of Andromeda (she was supposed to remain nude throughout the entire Kraken sacrifice scene). These elements were toned down in pre-production when the British censors reviewed the script and told the studio that they would give the film an "AA" (no one 14 and under admitted) rating if they put those scenes in the film.
Creator Backlash: Louis Leterrier disowned the final film, claiming "it's not my movie" and refused to return for the sequel.
Deleted Role: Apollo and Athena had major roles in the original cut, but the film was reworked. Apollo's role was heavily reduced, while Athena was almost cut completely. Additionally all the Gods originally had lines in the first scene on Olympus.
Old Shame: Alexander Siddig, who played Hermes, referred to this as "the lamest movie I ever made", claiming 50% of his performance was deleted.
Matthew Belamy was writing the score, but had to abandon midway through as Muse started a tour.
As detailed here, the film's original story was drastically different:
Perseus and Io's relationship was purely platonic; with a romance developing between him and Andromeda during his time in Argos. It would have ended with a Maybe Ever After situation between them.
Perseus's main motivation for going after the Gods in the original was to show that mankind did not need to rely on them for anything. Likewise he wished to save Andromeda because he felt that nobody should be sacrificed for the sake of the people. In the finished film, he just wants revenge on Hades.
Apollo and Athena had major roles, conspiring against Zeus and Hades. Apollo was originally the one who offered Perseus passage onto Olympus.
Zeus was far more villainous in the original cut. The film would have ended with Perseus going to Olympus and putting Zeus and the rest of the Gods on notice. Zeus would offer him a seat, but Perseus would refuse - saying his father is a dead fisherman.
The original idea for the movie was a Crossover Cosmology with Tiamat waging war against the Greek pantheon and Perseus being assisted by Thoth, Osiris, Marduk and Yahweh. He would also apparently have a romantic affair with some "Cthonian Earth goddess." (The filmmakers apparently have something against Andromeda for some reason...)
The Other Darrin: Rosamund Pike replaces Alexa Davalos as Andromeda. Also Ares was a minor background character in the first film, played by Tamer Hassan. In this sequel where he has a larger role, he's played by Edgar Ramirez.
Playing Gertrude: Zeus is meant to be Hephaestus's father. Bill Nighy is three years older than Liam Neeson.