The central twist of "North by Northwest" is the revelation that the man Roger Thornhill is mistaken for, George Kaplan, does not exist. He is a 'MacGuffin', a decoy agent invented by a U.S. intelligence agency, led by The Professor, to mislead foreign spy Phillip Vandamm and protect their real operative. This fact, revealed to Thornhill midway through the film, reframes his ordeal: he is not just a victim of mistaken identity, but a pawn in a deadly game between two governments.
The second major twist involves the character of Eve Kendall. After Thornhill falls for her, she appears to betray him to Vandamm at an auction. Later, it is revealed that she is, in fact, the real U.S. agent that the George Kaplan decoy was created to protect. Her relationship with Vandamm is part of her deep cover operation. To save her cover after Thornhill exposes it, The Professor stages a public 'murder' where Eve appears to shoot Thornhill in the Mount Rushmore cafeteria, firing a gun loaded with blanks. This allows them to get Thornhill to safety and convince Vandamm of Eve's loyalty.
The climax reveals the spies' objective: smuggling microfilm hidden inside a Pre-Columbian statue. Vandamm's henchman, Leonard, reveals he was always suspicious of Eve, having discovered her gun was loaded with blanks. This leads to the final confrontation on Mount Rushmore, where Vandamm attempts to murder Eve. The film ends with Thornhill, now a fully-fledged hero, rescuing Eve from the cliffside. The final shot abruptly cuts from him pulling her up the cliff to pulling her onto the top bunk of a train, now as his wife, followed by the symbolic shot of the train entering a tunnel, cheekily signifying the consummation of their marriage.