Halloween III: Season of the Witch ditches Michael Myers and instead has a story about evil masks that possess little children. The original plan was for a Genre Anthology film involving several unrelated stories, with the first just being longer. The movie tanked, and they haven't made another non-Michael version since.
It's also the last Halloween film that John Carpenter, who was not open to the idea of milking sequels, was associated with.
Titanic was this for James Cameron. He typically directs sci-fi films with a lot of action such as The Terminator, Aliens and Avatar so a tragic historical romance was a bit of an odd one out for him.
The original Alien might count as this for Ridley Scott. His forte is either historical epics (Gladiator, Kingdom of Heaven) or films with overt feminist themes (Thelma & Louise, GI Jane), so a horror film in space stands out.
Oh, you think that's bad? You should check out Disney's Pinocchio. That thing was dark both literally and metaphorically. There's a few really horrifying sequences such as the scene where a boy is seen turning into a donkey, made even worse when we see tons of other boys being turned into donkeys who are either sold to the salt mines or kept to pull the carriage to take more boys to the island to meet the same horrifying fate. Even more unusual for a Disney film, there are three different people who serve as villains (four if you count Monstro), and all of them get away with the things they do, including the ruthless coachmen who kidnaps boys and turns them into donkeys.
Another case of Disney doing something completly different was the 1954 version of 20,000 Leagues Under the Sea. The film was mostly a serious drama with a few bits and pieces of comic relief, and, even more unusual for a Disney film, there is no female lead, let alone any kind of romance. Probably the most unusual thing about it is the fact that it departs from the usual Happy Ending found in most Disney films, considering that in the end Nemo is finally ready to reveal his secret to the world, but ends up having to destroy everything on his island when it is unexpectedly attacked by an unidentified nation. In the process he is shot and killed. Aronnax, Ned, and Conseil escape, but they realize that the greatest discovery the world has ever seen has been lost forever. It's actually a pretty effective Bittersweet Ending.
Other unusual Disney work includes The Emperor's New Groove - which, in contrast to the examples above, is actually much lighter and more comical then standard Disney fare - and Atlantis: The Lost Empire, which is a sci-fi/action film without any songs instead of a fantasy musical. Atlantis also has barely any romance to speak of and the villain isn't revealed as such untill very late in the film.
Fantasia represented a fairly radical departure from Disney's usual fare when it was first released.
