Stan Javier homered and hit a tiebreaking double in the seventh inning, leading Mark Gardner and the San Francisco Giants past the Texas Rangers 4-3 before a sell-out crowd of 46,507.
The history-making night began with Darren Oliver throwing a low, inside fastball to Darryl Hamilton, ending the separation between leagues that traditionalists had preserved for more than century.
Hamilton followed with the first hit three pitches later, but the first double play took him off the bases - which were painted with a "First Interleague Game" logo. Players also wore interleague patches.
Javier, who has played nine seasons in the AL, homered in the third. His RBI double off Oliver (3-8) put the Giants ahead 4-3 in the seventh.
Gardner (7-2), who pitched for Kansas City in 1993, won for the first time since 22 May. Rod Beck pitched a scoreless ninth for his NL-leading 20th save, even though this one came against an AL team.
In Oakland, California, a rivalry previously confined to the World Series unfolded for the first time in the regular season as the Oakland Athletics, behind consecutive pinch hits by Patrick Lennon and George Williams, beat the Los Angeles Dodgers 5-4.
The Dodgers and A's met for the first time since Los Angeles defeated Oakland in the 1988 World Series. The teams also played in the 1974 Series, with the A's winning.
Dave Telgheder (2-3), who missed his last turn in the rotation because of a finger blister, helped the A's score one for the AL. He went 6 1- 3 innings, allowing four runs. Billy Taylor struck out two in a perfect ninth for his 12th save.