Pujols began 2008 by reaching base in 42 straight games, the longest streak to open a season since Derek Jeter reached base in the first 53 games of 1999. On June 11, he was placed on the DL with a strained left calf muscle. Although he was expected to miss three weeks, he was activated from the DL on June 26. Pujols hit his 300th home run against Bob Howry on July 4 in a 2–1 loss to the Cubs. He said after the game that to him it was "just another homer that goes out of the park. I'm happy to do it in front of our fans—they were waiting for it."
On September 11, in a 3–2 loss to the Cubs, Pujols hit his 100th RBI of the season against Rich Harden, making him the third player in major league history to start his career with eight seasons of at least 100 RBI (along with Simmons and Williams). He regretted that the milestone came in a loss, saying, "I wish it would have come with a great win. It would have been more special." In 148 games in 2008, Pujols batted .357 (second to Chipper Jones's .364 average) with 187 hits (third, behind Reyes's 204 and David Wright's 189), 44 doubles (tied with Stephen Drew and Aramis Ramírez for fourth in the league behind Berkman and Nate McLouth's 46 and Corey Hart's 45), 37 home runs (tied with Ryan Braun and Ryan Ludwick for fourth in the league behind Howard's 48, Dunn's 40, and Delgado's 38), 116 RBI (fourth, behind Howard's 146, Wrights 124 and Adrián González's 119) and 100 runs scored. He grounded into a National League-leading 27 double plays. Pujols won his second NL MVP Award, and he won the Silver Slugger Award for the fourth time in his career. He was named The Sporting News Player of the Year for the second time in his career. For his work off the field, he was named the 2008 winner of the Roberto Clemente Award. He considered having Tommy John surgery after the season but underwent nerve transposition surgery on his right elbow instead to ease discomfort.
In 2008, Pujols teamed up with St. Louis Soccer United, a group looking to bring a Major League Soccer (MLS) franchise to the St. Louis area. However, the group's bid for a franchise was unsuccessful, and a USL team (Saint Louis FC) was formed .
Pujols has earned praise from many of his fellow players and coaches. In 2008, he was named the most feared hitter in baseball in a poll of all 30 MLB managers. La Russa has called him "the best player I've ever managed." Votto referred to him as "one of the greatest hitters of all time." Larry Walker called him "a great hitter," and Brendan Ryan said, "He's the best there is." Fernando Viña said, while Pujols was with the Cardinals, "He's the face of the Cardinals."