St. Louis saw seven of its nine starters record an RBI, with Matt Carpenter scoring three runs in the win.
Marco Gonzales (1-2) recorded his first MLB win after he allowed one run on three hits with five strikeouts over six innings of work.
Tsuyoshi Wada (4-2) took the loss, yielding four runs -- three earned -- on five hits and three walks over six innings.
Jorge Soler and Chris Coghlan each had an RBI for the Cubs, who hit three homers in the Game 1 of the doubleheader en route to a 5-1 victory.
Each team put up a run in the first as Soler's double knocked in Arismendy Alcantara and Matt Adams added an RBI groundout in the home half.
Soler became the first player in Major League history to have an extra-base hit and RBI in each of his first four games.
With two outs in the fifth and a pair of runners on, Holliday launched a homer to right-center for a 4-1 lead.
Holliday then led off a nine-run eighth with a homer to center, and nine straight batters reached base from there as the Cards poured it on.
Coghlan had an RBI groundout in the ninth to account for the final margin.