Heisey's blast in the first inning gave the Reds a 4-0 lead and Ludwick's shot in the seventh wrapped up the scoring for Cincinnati, which won for the seventh time in eight games.
Brandon Phillips went 3-for-4 with two RBI and Devin Mesoraco added a solo homer for the Reds, who lengthened their National League Central lead over St. Louis to 1 1/2 games.
The Cardinals fell 4-0 to Philadelphia Saturday.
J.J. Hoover (1-0) took over for Cincinnati starter Mike Leake in the fourth inning and earned the victory with 1 1/3 scoreless frames.
Rockies starter Jeremy Guthrie (2-3) was pounded for six runs (two earned) in 10 hits over five innings.
Tyler Colvin supplied a pair run-scoring singles for Colorado.