Rose collected his first major championship after finishing at 1-over 281 on the tough Merion Golf Club course, overcoming five bogeys while draining five birdies.
Mickelson needed a birdie on the final hole to force a playoff but came up short on a long putt attempt and ended up with a bogey, carding a 4-over 74.
He settled for a record sixth runner-up finish at the U.S. Open without a victory, knotting with Jason Day (71) for second place at 3-over 283.
Rose had taken control of the leaderboard with birdies on Nos. 12 and 13, then surrendered it with bogeys on 14 and 16.
Mickelson and Day, however, couldn't capitalize. Day bogeyed 14 and 18, while Mickelson -- playing on his 43rd birthday -- bogeyed 13 and 15 to hand the lead back to Rose.
Mickelson needed to birdie any of the last three holes to pull into a share of the lead but couldn't produce one.