Misner came in as a pinch-hitter for Jonathan Aranda, who came in during the bottom of the seventh inning to do the same for Christopher Morel.
The home run off of Colorado Rockies relief pitcher Victor Vodnik gave the Rays a 3-2 win and their first of the season.
Misner had a stellar spring training for the Rays, slashing .394/.474/.667/1.140 in 33 at-bats.
He made his major league debut last season for the Rays, playing in just eight games.
The 27-year-old, after spending three years in college and five years in the minor leagues, finally has his career home run and it couldn't have come at a better time.
Tampa Bay had to move to the New York Yankees' spring training facility, George M. Steinbrenner Field, following the damage to Tropicana Field during Hurricane Milton.
The team will play there for the entire 2025 MLB season.