The first official major league game occurred on April 10, 2006, as the Cardinals defeated the Milwaukee Brewers 6–4 behind an Albert Pujols home run and winning pitcher Mark Mulder.

In 2004, then-Anheuser-Busch president August Busch IV announced that the brewing giant had purchased 20-year naming rights for the stadium.

August Busch IV and Anheuser-Busch share our vision for continuing that tradition for our great fans and the entire St. Louis community.

In June 2001, the Missouri state government signed a contract with the team, proposing a ballpark in downtown St. Louis, but a subsequent funding bill was struck down in May 2002, leaving the saga open.

[26] Construction on the seating area was completed in late May increasing the capacity for the May 29, 2006 game vs the Houston Astros with finishing touches performed throughout the year.

[29] In the first season of the new stadium, the Cardinals hosted the San Diego Padres in Games 3 and 4 of the National League Division Series.

Busch Stadium hosted only one postseason game in 2009, a 5–1 loss versus the Los Angeles Dodgers on October 10, to complete a sweep of the Cardinals.

In 2011, Busch Stadium hosted two postseason games in the National League Division Series versus the Philadelphia Phillies.

The Cardinals played two games in Busch Stadium against the Los Angeles Dodgers in the National League Division Series.

The Cardinals opened the National League Championship Series at Busch Stadium on October 11, 2014, against the San Francisco Giants.

The Giants won games 3, 4, and 5 in their home ballpark, to defeat the Cardinals in the NLCS 4–1, and move on to an appearance in the 2014 World Series against the Kansas City Royals.

The Cardinals hosted four postseason games at Busch Stadium in 2019, in the National League Division Series against the Atlanta Braves.

The Cardinals have allowed local high school teams to play each other on the field following select weekend afternoon games.

[30] Tickets for the match sold out within 20 minutes of going on sale, and Manchester City won 4–3[31] in front of a crowd of 48,263,[9] to date the 2nd largest attendance at a sporting event at the stadium.

On November 13, 2015, the United States Men's National Soccer Team defeated St. Vincent and the Grenadines 6–1 in the first match of the fourth round of qualifiers for the 2018 FIFA World Cup in front of a crowd of 43,433.

Another international friendly was hosted at Busch in 2016: Italian side A.S. Roma, bolstered by a goal from Bosnian star Edin Džeko, defeated Liverpool F.C.

[32] On March 9, 2016, the National Hockey League announced that the St. Louis Blues, for the first time in their 50-year history, would host an outdoor game.

Despite thick fog and spotty rain, Busch Stadium sold out to a crowd of 46,556 St. Louis hockey fans.

Southern Illinois University and Southeast Missouri State played each other in the first ever football game at Busch Stadium on September 21, 2013.

[39] 2019 saw the installation of LED floodlights with light-show capabilities, as well as the construction of the Budweiser Terrace in the right field upper deck.

Fans at the stadium have access to a large amount of food and drink options, ranging from standard ballpark fare like bratwurst, nachos and peanuts to St Louis-area favorites such as pork steak sandwiches and toasted ravioli.

Tickets for multiple all-inclusive areas are sold on a single game basis, with amenities running the gamut from the ritzy Champions Club (offering a multiple-course buffet, large screen televisions, a chance to get on television or radio as a broadcast booth is located inside the club, and a full bar) to the more family-oriented Scoreboard Patio (with table seating for four in center field and a cookout-style selection of food).

Operated by St. Louis-based Build-A-Bear, the store was first located in the right-field lower deck before it was moved to center field across from Ballpark Village in 2015 to allow it to be open on non-game days.

After St. Louis Post-Dispatch sportswriter Rick Hummel was honored with the BBWAA Career Excellence Award and induction into the National Baseball Hall of Fame and Museum in 2007, the Cardinals renamed the stadium's press box the "Bob Broeg-Rick Hummel Press Box", honoring the two local writers enshrined in Cooperstown.

During a weather incident during a July 2006 game vs the Atlanta Braves, portable concession stands were knocked over, the infield rain tarp was damaged, and plastic sheets used to protect the press box were dislodged.