Crosby scored 3:31 into the second period to tie the game 1-1 and reach the milestone. Conor Sheary assisted on the goal.
Crosby muscled a shot past Blues goaltender Jake Allen from the left side of the net, ending a 10-game goal-less streak.
"I still don't know how it trickled in. It seemed like it took forever. It's been a long 10 games, so it's nice to see one go in," Crosby said after the Penguins' 4-1 victory, according to the team's Twitter account.
Crosby added an empty-net goal in the third period. His father was at the game in St. Louis. Crosby said it was "special" to have him at the game.
"It was really nice. To have my dad here who was around for so many early mornings and sacrificed a lot so I could play hockey, it's special," he said, according to the team's Twitter account.
Thanks for the puck, ref.— Pittsburgh Penguins (@penguins) February 11, 2018
Sid's going to have to add that one to his collection. pic.twitter.com/zaNSApdCWZ
Crosby is also the 95th player in NHL history with 400 goals.
He has 19 goals this season. He led the NHL with 44 goals last season.
Only Joe Thornton, Patrick Marleau and Alex Ovechkin have more points among active players. Crosby was the top pick in the 2005 draft, and Ovechkin was No. 1 in 2004, but they both were rookies in 2005-06. They have been compared their whole careers, and after Crosby's goals Sunday, they were separated by only four points (1093-1088).