The Cardinals began their season at home against the San Diego Padres on March 31, following an 86–76 (.531) record and second-place finish in the National League Central in 2010.

Cardinals co-owner, team treasurer, and member of the board of directors Andrew N. "Drew" Baur died suddenly at his home at 66, in Gulf Stream, Florida on February 20, 2011.

[2][3] On October 18, 2010, manager Tony La Russa decided to return for his 16th season with the Cardinals after agreeing to terms for a new one-year contract, and a mutual option for a second year.

[9] Berkman, who was slated to play right field regularly for the first time since 2004, had slumped to a .248 average in 2010[10] and had hit particularly poorly after his midseason trade to the New York Yankees.

[12] On January 15, 2011, Albert Pujols, through his agent Dan Lozano, told the Cardinals that the date to report to spring training (February 18) was the deadline to reach a deal on a new contract.

[6] On November 16, 2010, the Cardinals signed starter Jake Westbrook to a two-year deal through 2012 for $16.5 million, with a mutual option for 2013, and a full no-trade clause.

[28] After missing only seven games while recuperating from surgery, Holliday returned to the lineup on April 10, singling and drawing two walks in a 6–1 victory over the Giants.

[29] Lance Berkman received the NL Player of the Week award on April 18, batting .417 (10-for-24), leading the majors with six HRs, 12 RBIs, and 1.167 Slugging percentage, and also having two multi-homer games.

[36] Rookie Eduardo Sanchez filled the role for a while in early May,[37] then Fernando Salas took the job and recorded seven saves in seven chances in the second half of the month.

The Cardinals were a strong 17–12 in May and finished the month 21⁄2 games ahead of the Milwaukee Brewers in the NL Central[40] despite numerous injuries to key players.

Albert Pujols struggled through a most uncharacteristic slump at the start of the season, going a career-worst 105 at-bats without a home run[41] and finishing May with an unusually low .755 OPS for the first two months.

[42] Tony La Russa, suffering from a severe case of shingles, missed six games, with bench coach Joe Pettini serving as acting manager.

[44] Tony La Russa managed his 5,000th major league game (2,676–2,320–4,  0.536 winning percentage) on June 10, but the milestone was marred by a shutout loss at Milwaukee.

He joined Wainwright, Freese, Nick Punto, Allen Craig, Gerald Laird, Bryan Augenstein and Eduardo Sanchez on the DL.

He walked 7 and struck out 17, with a 1.84 WHIP[54] Right-handed pitcher Brandon Dickson's contract was called up to fill the roster spot vacated by Franklin's release.

[60] The team made a major trade on July 27, a four-for-four swap, dealing disgruntled Colby Rasmus (hitting only .246), relievers Trever Miller and Brian Tallet, and starter P. J. Walters to the Toronto Blue Jays.

[66] The team made another trade on July 31, just before the non-waiver deadline, acquiring shortstop Rafael Furcal from the Los Angeles Dodgers in return for an AA-outfielder Alex Castellanos.

[69] On August 11 the Cardinals signed free agent lefty specialist pitcher Arthur Rhodes, previously released by the Texas Rangers.

"[74] Chris Carpenter and other veterans called for a closed, player-only team meeting, which was held the day after the Dodgers series ended.

[76] There were rumors,[77][78] later confirmed by owner Bill DeWitt,[79] that with the Cardinals seemingly out of playoff contention, they had discussed trading Lance Berkman to the Texas Rangers.

They ended the month on a positive note, taking three of four from the Pirates and sweeping the Brewers in Milwaukee Aug 30 – September 1, improving their chances of making the playoffs to 4.3%.

[88] On the 16th an error by right fielder Corey Patterson allowed the Phillies to tie the game 2–2 in the bottom of the ninth, but the Cardinals scored on RBI hits from rookie Adron Chambers and Tyler Greene in the 11th and hung on to win 4–2.

[89] On the 19th the Cardinals escaped with a 4–3 victory over the Phillies when Octavio Dotel got Hunter Pence to ground out in the bottom of the ninth with the tying run on base.

[90] The Braves went 3–4 over this same stretch of games, losing to the Marlins on September 19 when Omar Infante hit a game-winning two-run homer in the bottom of the ninth inning.

With their final regular-season game freshly on the books, Cardinals players and fans anxiously watched the still-ongoing Braves-Phillies match in Atlanta that was now in extra innings.

After Roy Halladay struggled in the first, allowing a three-run homer to Lance Berkman, he settled down, at one point retiring twenty-one Cardinal hitters in a row.

The October 7, Game 5 winner-take-all in the NLDS pitted Cardinals' ace Chris Carpenter vs. Roy Halladay, his best friend off-the-field for the Phillies, at Citizens Bank Park.

Later, with the score tied 9–9, Freese hit a lead-off walk-off home run to dead centerfield in the 11th, off Mark Lowe at 11:39 pm CDT.

[120] Although Dave Duncan did not officially retire, he took an extended leave of absence to tend to his ailing wife and his assistant Derek Lilliquist was nominated as his substitute.

Saves/Opp: 47/73 (64.4%)   1st Batter / Retired: 329/462 (71.2%) Holds: 84 Inherited Runners/Scored: 68/231 (29.4%) [155] (through Sep 26, last loss) Games lost by bullpen: 30  Salas (6), Franklin (4), Dotel (3), Rzepczynski (3), Boggs (3), Motte (2), Batista (2), Tallet (1), Augenstein (1), Sánchez (1), Miller (1), Valdés (1), Rhodes (1), McClellan (1)