Ability over Appearance: Originally, Perseus was envisioned as being more of a young slender man. Louis Leterrier had watched Sam Worthington in the film Somersault, and thought that he would be ideal, and was therefore somewhat taken aback when he met Worthington. The actor had bulked up considerably for his roles in Avatar and Terminator Salvation.
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.
Follow the Leader: Followed-up on the rekindling of interest in Greco-Roman set films by Gladiator as well as arguably even more prominently the popularization of a heightened and fantastical style of 300.
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," with Andromeda being relegated to be a spoiled princess with a male harem.
Franchise Killer: A sequel for the film, titled Revenge of the Titans was in production, and the plot would have involved the resurrection of the gods. However, it was later scrapped, due to the poor reception of this film.
McLeaned: The first film has Io being resurrected at the very end to live Happily Ever After with Perseus...only for the sequel to open with him at her grave. Gemma Arterton did not want to return for the sequel and rather than creating The Other Darrin for a second lead character, they just killed her off.