Palmeiro connected off Bobby Ayala (0-5) after Harold Baines opened the inning with a single. Ken Griffey Jr. had given Seattle the lead in the top of the 10th with his second homer of the game, a solo drive off Norm Charlton (1-1).
Palmeiro's 14th homer marked yet another collapse by Seattle's leaky bullpen and ended a second straight slugfest between the teams, who combined for eight homers Monday night in the Orioles' 10-9 victory.
"They're probably the best offensive team in all of baseball, but we're not too shaky," said Palmeiro, who also tripled and singled. "The last two nights we've been able to keep up with them."
Griffey had three hits, including a three-run homer in the third and his 21st of the season in the 10th. Alex Rodriguez hit his 21st homer for the Mariners, who have a team-record 13 homers in their last three games and a major league-leading 97.
"The home runs don't matter. We just lost another game," Rodriguez said. "Give me some wins. The personal stuff doesn't matter."
Cal Ripken's 375th home run, a two-run shot in the second, moved him past Rocky Colavito into 39th place on the all-time list.