The 30-year-old Lincecum also no-hit the Padres last July as he became the second pitcher in history to no-hit the same team twice. He joins Addie Joss who no-hit the White Sox in 1908 and 1910.
Lincecum, who has two World Series championship rings, stuck out six batters and walked one in front of a crowd of 41,500 at AT&T Park.
He capped the no-hitter by getting Padres batter Will Venable to ground out in the ninth. Giants second baseman Joe Panik scooped up the ball then threw to first baseman Buster Posey to end the game.
San Diego came into Wednesday's game as the worst offensive team in Major League Baseball, ranking 30th out of 30 teams in batting average (.216) and runs (239).