Rodriguez missed New York's first 28 games following hip surgery. He chose a less invasive operation that allowed him to return much sooner than the four-month absence doctors had originally expected. Another operation may be needed after the season.
Friday's appearance was also the first for the slugging superstar since he admitted using steroids while a member of the Texas Rangers from 2001-03. That revelation has cast a shadow on a career that includes three MVP awards.
Rodriguez's return came one day after Los Angeles Dodgers star Manny Rodriguez was suspended 50 days for a violation of baseball's drug policy.
With Jeremy Guthrie starting for Baltimore, Johnny Damon and Mark Teixeira drew one-out walks in the first inning. That brought up Rodriguez, who swung at Guthrie's first offering and sent it deep to left.
He followed that impressive 2009 debut by striking out in both the third and fifth innings and then grounding out in the seventh.
Damon doubled home a run in the seventh for New York, which ended a five-game losing streak and moved to within one game of .500.
The Rodriguez homer overshadowed a tremendous, nine-inning pitching performance by CC Sabathia (2-3), who allowed four hits and struck out 12 while throwing 112 pitches.
Guthrie (2-3) surrendered seven hits and the three runs over seven innings.