The Baltimore veteran lined a 2-2 pitch from Mariners' starter Joel Pineiro into the left-field corner to reach the milestone. The run-scoring hit gave the Orioles a 4-1 lead.
Palmeiro, 40, is just the fourth player with 3,000 hits and 500 homers along with Hank Aaron, Willie Mays and Eddie Murray. His 566 career home runs are the ninth-most in major-league history and he is the second player in an Orioles uniform to reach the 3,000th hit plateau, joining Cal Ripken, Jr.
Murray, who spent the majority of his career with Baltimore, recorded his 3,000th hit with the Cleveland Indians in 1995.
The last player to record 3,000 hits was Rickey Henderson, who did it with a double off Colorado's John Thomson while with the San Diego Padres on Oct. 7, 2001.