After a fairly comfortable victory in the first set with 6-3, Williams was put against the wall in the second.
The 38-year-old American ended up 0-4 behind in the tiebreak of the second set.
When she reduced to 1-4, she wrote out the relief that she had finally scored.
However, that did not help.
The Greek kept the game together and managed to win the tiebreak 8-6.
Sakkari took Williams serve in the beginning of the third set and put real pressure on last year's second in the tournament.
But Serena Williams took a couple of steps forward on the track, turned around and played home the set with the numbers 6-3.
Thus, Serena Williams took revenge on the Greek, who 13 days ago defeated Williams in a Cincinnati. The 23-time Grand Slam winner and finished second in the US Open the last two years and won most recently in 2014.