Holliday's shot hit the Marlins clubhouse beyond the left field wall. The Marlins and Cardinals share the complex.
Holliday later singled and scored in the fourth inning.
That was all the work the 12-year veteran needed for the day.
''Some of them need to go nine (innings) and some of them maybe not so much,'' manager Mike Matheny said. ''He puts together a homer and another laser - that's a good day to just get out.''
Cardinals starter Carlos Martinez gave up one run and three hits in six innings. He walked none and struck out four.
Martinez finished his outing by throwing a fastball past Yoenis Cespedes.
''That's a good fastball hitter,'' Matheny said. ''I thought it was just a great outing.''
Colon allowed three runs and seven hits in six innings.
Neil Walker doubled and scored the Mets' run.
Playing his first Grapefruit League game since straining his knee on March 10, Mets shortstop as Asdrubal Cabrera went hitless in three at-bats.
St. Louis won for only the second time since March 12. The Mets' loss broke a string of three consecutive ties, and left them winless in 11 games.
Mets: Colon threw 68 of his 92 pitches for strikes. Afterward, Colon said he could pitch out of the bullpen for New York's first two games of the season in Kansas City.
Cardinals: Martinez will pitch in a minor league game for St. Louis on Saturday before rejoining the club for the season opener in Pittsburgh.
Cardinals: Catcher Yadier Molina was scratched from the starting lineup because of a bruised toe suffered in the weight room. Matheny said he is day to day. ... Reliever Jordan Walden made his first appearance since March 21. The Mets loaded the bases against Walden on two hits and a hit batter but couldn't push across a run. Walden hasn't allowed a run in six Grapefruit League appearances, but his health remains a concern.
St. Louis third base coach Jose Oquendo conceded that if his knee doesn't heal properly during his upcoming medical leave of absence, he may be forced to retire.
''I don't know yet,'' he said. ''I can't tell what I'm going to do two to three months from now.''
Oquendo underwent two surgeries on his right knee during the past year, including one a couple weeks ago. He's hoping the medical leave, which the Cardinals announced on Sunday and expect to last the entire season, will help him avoid having to undergo knee replacement surgery.
Mets: New York and Sean Gilmartin host the Marlins.
Cardinals: Adam Wainwright starts against Stephen Strasburg and the Nationals.