The Dodgers have hit 250 on the year, surpassing the Houston Astros' previous record of 249, which they set in 2000.
Pederson opened the game with his eighth leadoff homer of the season to match the record, then set the mark with a two-run blast in the fourth inning. It was Pederson's fifth multihomer game of the year.
Pederson has been using one of Andre Ethier's old bats since seeing his former teammate during last weekend's series in Arizona, where Pederson hit a tiebreaking homer in the 11th inning Sunday.
"I told him there better be some more coming,'' Pederson said of the loaned lumber.
Ethier, who is from Phoenix, retired nearly two years ago after spending his entire 12-year career with the Dodgers.
Pederson slugged five homers and a double in a string of six at-bats going back to Sunday. He sat out Tuesday, one day after crashing into the outfield wall to make a catch.
"He's streaky,'' Dodgers manager Dave Roberts said. "When they make a mistake out over the plate, it's a home run. He's feeling really good. He's found consistency.''
The Dodgers slugged 12 homers in the series -- falling two shy of their franchise record for a three-game set -- while outscoring the Rockies 28-15.
"A lot of good players one through 15,'' Pederson said in explaining the home run numbers. "Guys who got called up contributed. It's a special unit we have.''
The Dodgers' feat came just four days after the Minnesota Twins broke the American League and major league record with their 268th homer of the season.
NL teams, though, are at a natural disadvantage in the chase for home runs because of the presence of the pitcher in the lineup. The Dodgers have only one home run from a pitcher this year and none from a designated hitter in their interleague games played in AL ballparks, whereas the Twins have had 44 from their DH spot.
Cody Bellinger leads the Dodgers with 44 homers this season, followed by Max Muncy with 33 and Pederson's 32.
The Associated Press contributed to this report.
Pederson crushes two homers, Dodgers break NL single-season record
Joc Pederson goes deep twice, and his second home run sets the National League record for home runs by a team in a season in MLB history.