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.
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 completely different was the 1954 version of Twenty Thousand 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.
Part of why the James Bond film Licence to Kill was poorly received in its original release (at least in the US) was how extremely atypical it was compared with previous Bond films. This time, Bond was not on a mission with MI6, fighting for king and country, he was on his own, fighting for himself and his friends in a Roaring Rampage of Revenge.
This is explicitly stated to be the reason why Marvel made the Guardians of the Galaxy movie for the Marvel Cinematic Universe. Each of the previous movies depict the origins of the Avengers, with top of the line Marvel characters such as Captain America and Thor, culminating in The Avengers movie. Guardians of the Galaxy is pretty much a gathering of C-list and D-list Marvel characters that nobody would have expected to be featured in a film.
The 2014 Seltzer and Friedberg movie Best Night Ever is almost a total departure from their normal film style. For one while it is a comedy it isn't a spoof: while it is clearly influenced in style by The Hangover being set around a wild weekend in Vegas to celebrate an upcoming wedding it tells its own story with original characters. It also much more realistic, low key and character driven (!) than any previous Seltzer and Friedberg film with little to no pop culture reference and no cartoony humour. About the only traditional Seltzer and Friedberg touch is a lot of gross out humour and nudity.