''I put myself in the pitcher's shoes in that situation,'' Santander said through a translator. ''Knowing that he wanted to come in, trying to jam me, trying to make me hit a soft grounder to force a double play. I was really able to get my hands in and focus on that. I hit the ball really well.''
New York lost for just the second time in 11 games and is still a major-league best 28-10. The Yankees fell to 18-1 when scoring five runs or more this season.
The Yankees were down to their last out in the ninth when DJ LeMahieu hit an RBI single off closer Jorge Lopez that tied it at 6.
The Orioles answered when Austin Hays reached on a throwing error by third baseman Josh Donaldson, who had pinch-hit in the top half of the inning. One out later, Trey Mancini singled and Santander followed with a drive to left field for his seventh homer of the season.
When Santander connected, it had plenty of distance - the only question was whether it would be fair or foul, and it easily was inside the pole at Camden Yards.
''Last two nights, we lost two one-run games,'' Orioles manager Brandon Hyde said. ''I thought today was some of our better at-bats of the season.''
Giancarlo Stanton homered over the left-field wall, which was moved back 26 1/2 feet since last year and was called ''a travesty'' by New York slugger Aaron Judge this series. Stanton became the first Orioles opponent to clear that fence. He has 11 home runs and he leads the league with 35 RBIs.
Felix Bautista (1-1) picked up the win for the Orioles.
The Yankees still finished their eight-game road trip 6-2.
''Any time you go out on the road and throw a 6-2 out there, you'll take that,'' manager Aaron Boone said. ''Look forward to being back at Yankee Stadium.''
Orioles reliever Bryan Baker entered with a bases-loaded jam and no outs in the sixth. He struck out Gleyber Torres and Aaron Hicks before allowing a two-run single to Isiah Kiner-Falefa that boosted New York's lead to 5-3.
The Orioles responded in the bottom half on an RBI single by Tyler Nevin, a pinch-hit sacrifice fly to Cedric Mullins and a single by Rougned Odor off Chad Green that gave Baltimore a 6-5 lead.
Green then left the game with right forearm discomfort and will be re-evaluated on Friday.
''With an arm injury, you're not really sure what could happen or what's going on,'' Green said. ''We'll get it checked out tomorrow and just go from there.''
The Yankees took a 2-0 lead in the first off Orioles left-hander Bruce Zimmermann on an RBI single by Stanton off the left-field wall.
The Orioles tied it at 2 in the second on the two-run shot by Robinson Chirinos off Yankees left-hander Jordan Montgomery. It was the first home run by a Baltimore catcher at home this season.
Baltimore took the lead in the third when Santander doubled and scored on a single by Jorge Mateo.
It was just the second time Montgomery allowed more than two runs over eight starts this season.
''I just want one pitch back to Chirinos,'' Montgomery said. ''Other than that, my stuff was pretty good.''
Stanton delivered again and tied the game with a solo shot in the fourth that traveled 392 feet.
Yankees first baseman Anthony Rizzo was ejected in the seventh for arguing with home plate umpire Manny Gonzalez after a swinging strikeout. ''It's really frustrating,'' Rizzo said.
The Orioles turned double plays in the second, third and seventh innings and lead the league with 49.
Yankees: OF Tim Locastro (back strain) is progressing well, swinging the bat and hitting off a tee, but there is no timeline for when he will be back in the lineup.
Orioles: 1B Ryan Mountcastle (left wrist, forearm) will likely come off the IL Saturday.
Yankees: LHP Nestor Cortes (2-1, 1.35) ERA will start the series opener Friday against the Chicago White Sox and LHP Dallas Keuchel (2-3, 5.54). Cortez has allowed two earned runs or fewer in each of his seven starts this season.
Orioles: RHP Tyler Wells (1-3, 4.18 ERA) opens the series against the Tampa Bay Rays and LHP Jalen Beeks (1-0, 1.72). Wells has a career 7.04 ERA in his five career games (one start) against the Rays.
More AP MLB: https://apnews.com/hub/MLB and https://twitter.com/AP-Sports
Copyright 2022 STATS LLC and Associated Press. Any commercial use or distribution without the express written consent of STATS LLC and Associated Press is strictly prohibited.