Actors and movies they did outside of their associate genre.

[RobbieL2415]

For example:

John Travolta, Carrie (1976)
Vince Vaughn, Jurrassic Park: The Lost World (1997)
Carey Elwes, Saw (2004)
Johnny Depp, A Nightmare On Elm St. (1984)
Matthew Broderick, Godzilla (1998), Inspector Gadget (1998)

[Max Rockatansky]

Keanu Reeves in Bram Stoker's Dracula which was more or less a horror movie...with an equally horrific performance by Reeves who almost dragged the whole thing down with him.

[golden eagle]

Jim Carrey starred in the horror film The Number 23, and was a TV movie Doing Time On Maple Drive In the early 90s.

[KeithE4Phx]

John Wayne, as Genghis Khan, in The Conqueror (1956). 

A tragic movie all the way around.  Not only was Wayne miscast, but many cast and crew members, including director Dick Powell and Wayne himself, later died of cancer.  This was allegedly because the film was shot downwind from a nuke test site in Nevada, although Wayne was also a heavy smoker.

[wanderer2575]

Jim Carrey did a dramatic role in The Truman Show.

Robin Williams was perhaps best known for high-energy comedy, but he had a number of dramatic movie roles.

One might nominate most of the entire main cast of Airplane! (Robert Hayes, Robert Stack, Lloyd Bridges, Peter Graves, and Leslie Nielsen), although the genius of the movie is that they all played their roles in straight dramatic fashion, not as slapstick comedy.  (I omit Julie Hagerty because she had done other comedy.  And of course this film relaunched Leslie Nielen's film career as a comedy actor.)

If you include television, Jonathan Winters' first role on film was a dramatic performance opposite Jack Klugman in the original Twilight Zone episode "A Game of Pool" written by George Clayton Johnson.

John Wayne, as Genghis Khan, in The Conqueror (1956). 

A tragic movie all the way around.  Not only was Wayne miscast, but many cast and crew members, including director Dick Powell and Wayne himself, later died of cancer.  This was allegedly because the film was shot downwind from a nuke test site in Nevada, although Wayne was also a heavy smoker.

And made worse because RKO Studios owner Howard Hughes had several dozen tons of the radioactive dirt from Snow Canyon, UT (where a significant portion of the film was shot) shipped to Hollywood to recreate the desert location on a soundstage for retakes and other scenes.

[SSOWorld]

One might nominate most of the entire main cast of Airplane! (Robert Hayes, Robert Stack, Lloyd Bridges, Peter Graves, and Leslie Nielsen), although the genius of the movie is that they all played their roles in straight dramatic fashion, not as slapstick comedy.  (I omit Julie Hagerty because she had done other comedy.  And of course this film relaunched Leslie Nielen's film career as a comedy actor.)

[TheHighwayMan3561]

Al Pacino, "The Insider" and "Any Given Sunday"

[roadman65]

Ricardo Montablan when he appeared in a movie Dominque which was outside his usual villainous roles and adventure or drama he always did.  In that movie was religious themed and though maybe considered a drama, but in nature pictures of convents and churches can be looked at as a separate genre altogether.