The left-hander will make his first start since September on Wednesday at Philadelphia.
"I think he's ready," general manager John Mozeliak said. "Not only what we've seen but just what he's telling us and how he feels has been something of a benchmark.
"If he feels like he's in the right place right now, he's ready for this opportunity."
The former 20-game winner takes the rotation spot of Mitchell Boggs, who was demoted to Triple-A Memphis before St. Louis' 7-1 loss to the Chicago Cubs on Sunday. The Cardinals also activated shortstop Cesar Izturis from 15-day disabled list, placed outfielder
Brian Barton on the DL with an injured hand and recalled outfielder Joe Mather from Memphis.
Mulder, coming back from two shoulder operations, allowed two runs and four hits in 1 1/3 innings in the first two relief appearances of his career. He made three starts last September and was 0-3 with a 12.27 ERA before undergoing a second operation.
This time, the Cardinals believe he's better equipped although Mulder's return was not bump-free. The team halted Mulder's first rehab stint because he had problems reaching his pre-surgery arm slot, and he made it back to the majors pitching with an approach that is more at a three-quarters angle.
"Obviously, every decision you make there's risk," Mozeliak said. "In this case, we're pretty confident he's ready to go."
The Cardinals minimized Mulder's woes in his last outing because the balls were not solidly hit.
"He pitched much better than his line read," Mozeliak said. "More important, it wasn't like he was hit very hard."
Boggs was a pleasant surprise before giving up 11 runs, 10 earned, over six innings in an 11-1 loss to the New York Mets on Thursday. Boggs is 3-1 with a 6.59 ERA in six games, including five starts, and will start on Wednesday in the minors.
Izturis, who had been sidelined with a hamstring strain, and Mather, beginning his second stint with the Cardinals, were in the lineup against the Cubs. Mather was in left field and batted leadoff, going 1-for-4 with two strikeouts. Izturis was in the seventh spot and went 0-for-4.
Izturis said he's been ready to go for the last several days. The Cardinals placed him on the DL because they didn't feel they could afford to be shorthanded for a week or so.
Mather, 25, was batting .303 with a team-high 16 homers and 38 RBIs for Memphis. In 13 games earlier this season, he hit .229 with one homer and three RBIs.
Information from The Associated Press contributed to this report.