The blast off Baltimore starter Wei-Yin Chen was Rodriguez's 16th of the year and the 645th of his career. He previously hit 189 homers with the Mariners and 156 with the Rangers.
"I had no idea I had 300, but the only numbers we're worried about right now are W's," Rodriguez said. "Whatever you're going to do for the year is already done. Numbers are done, stats are done; we're worried about one thing, and that's winning games. That makes it a lot of fun, so a lot of good things happened today."
Rodriguez is sixth on the Yankees' all-time list, trailing Hall of Famers Babe Ruth (659), Mickey Mantle (536), Lou Gehrig (493), Joe DiMaggio (361) and Yogi Berra (358).
The homer was the first for Rodriguez since he was activated from the disabled list, missing time with a fractured left hand, and catcher Russell Martin said that Rodriguez's presence in the order has been "huge" for the Yankees.
"He just extends the depth of our lineup," Martin said. "He matches up well against anybody, especially once he gets going a little bit. He hasn't had that many ABs, but you can tell that he's starting to take better swings."
Rodriguez also had one other notable milestone in the game. His second-inning single was his 2,877th hit, surpassing Mel Ott for sole possession of 39th place on the all-time list.
Owning an 11-game hitting streak, Rodriguez is two hits shy of tying Frankie Frisch for 38th all-time, and six hits shy of tying Zack Wheat for 37th place.