The right-hander fanned rookie Michael Chavis looking with a 92 mph fastball for the historic strikeout. Hernandez is the fourth active pitcher to reach the mark, behind the Yankees' CC Sabathia, Houston's Justin Verlander and Washington's Max Scherzer.
Hernandez added one more strikeout -- his third of the game -- before he was chased by the Red Sox after giving up seven runs on six hits and three walks in just 2 1/3 innings.
At 33 years, 33 days of age, King Felix is the sixth youngest to get to 2,500 strikeouts, trailing Nolan Ryan (31.101), Walter Johnson (31.197), Pedro Martinez (32.221), Tom Seaver (32.287) and Bert Blyleven (33.000).
"I did. Finally,'' Hernandez said smiling of reaching the mark. "Hopefully I can play a few more years to get to 3,000.''
The Associated Press contributed to this report.