Harris, 60, will play the presidential candidate and longtime Arizona senator in HBO's upcoming film about the 2008 presidential election.
Game Change, based on the book by Mark Halperin and John Heilemann, will center on McCain's 2008 run for the White House, from his selection of Palin as his running mate to losing to President Barack Obama.
The film will re-team director Jay Roach and screenwriter Danny Strong, whose 2008 HBO film Recount documented the chaos following the 2000 presidential race between Al Gore and George W. Bush and won three Emmys. Roach will also executive produce and Strong will co-executive produce.
Harris, a four-time Oscar nominee, most recently starred in Peter Weir's The Way Back.