The 28-year-old closed with a two-under-par 68 at Shinnecock Hills on Sunday to finish one shot ahead of Fleetwood, who was chasing his first Major title.
Fleetwood fell narrowly short as he carded a round of 63, matching the lowest ever recorded in the competition, but a birdie putt on the last saw Koepka come out on top.
Further down the board, world number one Dustin Johnson shot 70 to finish third, three behind the winner, while Justin Rose dropped down to 10th despite starting the day one shot adrift of a four-way tie for the lead.
US OPEN LEADERBOARD
1. Brooks Koepka (+1)
2. Tommy Fleetwood (+2)
3. Dustin Johnson (+3)
4. Patrick Reed (+4)
5. Tony Finau (+5)