On April 4, 2001, Rentería went three-for-five and hit a 432-foot home run off Denny Neagle in a 13–9 loss to Colorado at Coors Field. On April 18, he walked and scored the winning run on a wild pitch by Randy Johnson in a 3–1 victory over the Arizona Diamondbacks. He had a pinch hit single on May 10 against Pittsburgh that provided the winning run in an 11–5 victory. His RBI single off John Rocker of Cleveland on July 8 gave the Cardinals a 4–3 victory. However, his batting average was only .226 by July 26. Rentería batted .299 in his last 58 games, though, to raise his batting average to .260 by the end of the season. During those games, Rentería had a ten-game hitting streak from August 8 to 17. Rentería finished the season with seventeen stolen bases, which led the Cardinals. In Game 3 of the 2001 NLDS, Rentería hit his first playoff home run, off Brian Anderson of Arizona, in a 5–3 loss. However, the Diamondbacks defeated the Cardinals in five games on their way to winning the World Series.