Colon, 45, reached the milestone when he struck out second baseman Max Muncy in the first inning.
Colon is the 34th pitcher in MLB history with 2,500 strikeouts. He is tied with Hall of Famer Juan Marichal for most wins by a pitcher from the Dominican Republic with 243.
After tossing at least five innings in 10 of 11 starts, Colon left Tuesday's game in the fourth inning with the Rangers trailing 7-2. He was tagged for season highs in runs (eight) and hits (nine) in 3⅓ innings, giving up home runs to Joc Pederson, Muncy and Yasiel Puig.
The Dodgers won 12-5.
"They took advantage of me. They got heated up good," Colon, who is in his 21st major league season, said through a translator. "That's what happened, so I couldn't do [anything]. They were very aggressive, and I couldn't hold them."
Muncy, when asked if Colon was the oldest pitcher he has ever homered against, said, "Uh, yeah -- unless you count my dad in batting practice or something."
The Associated Press contributed to this report.