The National League had gone into the ninth with a 2-1 lead in hopes of ending the American League's eight-game winning streak.
Hoffman, the Padres' lone representative in the game, retired the first two hitters he faced in the ninth on come-backers to the mound.
With Florida third baseman Miguel Cabrera guarding the line in a "no doubles" defense, Chicago White Sox first baseman Paul Konerko hit a ground ball single to left through the large 5.5 hole. Toronto third baseman Troy Glaus followed with a ground-rule double forcing pinch-runner Jose Lopez of the Seattle Mariners to stop at third.
That brought up Texas Rangers shortstop Michael Young, who tripled to center scoring both Lopez and Glaus. The decisive hit earned Young the game's Most Valuable Player award.
The inning ended when Minnesota catcher Joe Mauer became the third hitter in the inning to bounce out to Hoffman. But the damage had been done. Yankees closer Mariano Rivera worked a scoreless bottom of the ninth to pick up the save.
The American League struck first in the second inning against Brad Penny an inning after the Dodgers starter had opened the game by striking out the side -- Seattle's Ichiro Suzuki, the Yankees' Derek Jeter and Boston's David Ortiz -- on a run of fastballs.
The game's first run came on a homer by Angels' left fielder Valdimir Guerrero in the second.
The National League tied the game in the bottom of the second against American League starter Kenny Rogers of the Detroit Tigers. Again, it came on a long ball when New York Mets third baseman David Wright homered with one out.
The National League took a 2-1 lead in the bottom of the third against Roy Halladay of Toronto.
Washington Nationals left fielder Alfonso Soriano singled to left with one out and immediately stole second. Mets center fielder Carlos Beltran followed with a line drive single to center, but a perfect throw by Toronto's Vernon Wells nailed Soriano at the plate trying to score.
But Beltran took second on the throw home, stole third and scored on a wild pitch by Halladay.
The game remained scoreless until the ninth.
The American League had only three hits from the third to eighth innings. The National League didn't get a hit after getting three against both Rogers and Halladay as each worked two innings. In fact, only two National League hitters reached base over the final five innings -- one on a walk and the other on a ninth-inning error.
Toronto reliever B.J. Ryan was credited with the win after pitching a perfect eighth.
Konerko was the only hitter in the game with two hits.
The game was the fifth All-Star Game played at Pittsburgh, which became the first city to host All-Star Games at three different ballparks -- Forbes Field, Three Rivers Stadium and PNC Park.