"It's the mark of a great career," said manager Tony La Russa.
With the home run, Pujols became the fifth-youngest player to reach 300 home runs.
However, whatever elation Pujols had when he hit the milestone shot vanished by the end of the night. Losing to the Cubs, 2-1, the Cardinals fell to 3 1/2 games out of first place in the National League Central.
"It doesn't matter," Pujols said. "Three hundred home runs, obviously it's a great honor to be named with some of the great players in the game. I would have taken 1-for-4 with a win, that's more important."
Instead, as Pujols bluntly put it, "It's just another homer that goes out of the park."
While Ken Griffey Jr. celebrated his 600th home run last month, Pujols said the satisfaction of reaching a milestone won't happen until he gets to where the leaders are.
"What milestone?" Pujols said. "It's 300 home runs. The milestone is 500, 600, like those guys have. Obviously, I think that's a long way from 300."
In his eighth year as a Cardinal, Pujols now defines what constitutes a great hitter.
Pujols has racked up accolade after accolade, making him one of the more feared hitters in all of baseball, and is the only player in the history of Major League Baseball to hit at least 30 home runs in each of his first seven seasons.
Pujols is tied with Joe DiMaggio with 100 RBIs in each of his first seven seasons and is behind Al Simmons (11) and Ted Williams (8). There is a chance he will also eclipse 100 walks for the first time in his career this year, as well.
It didn't take long for Pujols to get his home run stroke going in the Majors. In just his fourth game, Pujols hit his first home run -- a two-run home run off Arizona's Armando Reynoso.
Pujols ended his first year with 37 home runs and 130 RBIs to win the National League Rookie of the Year. But the hurting for pitchers didn't end there.
Two years later, Pujols hit his 100th home run, which came off Odalis Perez on July 20. No. 200 came on Sept. 30, 2005 while facing the Reds' Matt Belisle.
Wade Miller (6) and Perez (5) are Pujols' favorite targets when it has come to hitting home runs. Pujols has relished hitting homers off right-handed pitchers, belting 229 in his career.