He accounted for all four runs that Santos surrendered in four shaky innings by hitting a solo homer and a two-run double, then scoring on So Taguchi's single.
With those two big hits, Grudzielanek improved his career batting average against Santos to .565.
"I don't know what it is," said Grudzielanek, who is 13-for-23 against his favorite pitcher. "I'm sure he's trying to figure it out."
Santos hasn't been able to put his finger on it.
"That's the guy I hate to face when the game is on the line," Santos said. "I don't pitch him the same way every time, but he always seems to get hits off me."
Grudzielanek said there's just something about Santos' delivery that he likes.
"I just see the ball out of his hand and I can tell what it is right away, and obviously, you can see that," Grudzielanek said.
Nunez's bloop single off Wise (4-4) landed in front of center fielder Brady Clark, who was playing deep, pulled up, grabbed the ball on the bounce and fired late to home plate, where Grudzielanek scored from second.
Brewers manager Ned Yost insisted his center fielder wasn't playing too deep.
"You can't have your defensive guys everywhere. It wasn't like Brady was playing with his back against the wall. Brady came in a few steps," Yost said. "He just hit it under the coverage. It would be nice if you could have 15 guys out there, but you can't."
Grudzielanek had just stolen second after reaching on a fielder's choice. Nunez took second on the throw and scored on Taguchi's ground-rule double to make it 6-4.
"It couldn't come at a better time, he just had a huge night," Cardinals manager Tony La Russa said of Grudzielanek, a Milwaukee native who had 10 family members in attendance.
Grudzielanek, Nunez and Taguchi -- the Nos. 5-7 hitters -- combined to go 8-for-13 with all eight RBI.
"That's huge because opposing pitchers are always worried about Albert Pujols and Jim Edmonds. These guys give you great at-bats," said St. Louis starter Matt Morris, who failed to get his 100th career victory because of an error by Pujols that led to two unearned runs in the fifth.
After Geoff Jenkins hit a two-run bloop single in the first, Grudzielanek cut the Cardinals' deficit in half with his seventh homer off Santos in the second inning. He added a two-run double in the fourth and scored on Taguchi's single, giving Morris a 4-2 cushion.
Santos allowed four earned runs and five hits in four innings. He was lifted for pinch-hitter Chris Magruder when the Brewers loaded the bases with one out in the fourth.
Magruder dribbled a ball to first baseman Pujols, who got the forceout at home plate despite an off-target throw that forced catcher Mike Mahoney to sprawl out with his toe touching the plate. Clark ended the threat by lining out to Nunez at third.
An error by Pujols an inning later led to two unearned runs that tied the game at 4. Carlos Lee and Wes Helms each had RBI singles in the inning that prevented Morris from improving to 13-4 on the season and 12-4 lifetime against the Brewers.
Morris allowed four runs -- two earned -- on six hits and three walks in six innings.
The Brewers (56-57), who haven't had a winning season since 1992, failed to move above .500 for the first time since May 27, when they were 24-23.
- RHP Anthony Reyes, the top pitching prospect in the Cardinals' farm system, will make his major-league debut Tuesday night against the Brewers. With one scheduled day off this month, the Cardinals are giving him the spot start so the rotation gets some rest. The 23-year-old is 7-4 with a 3.44 ERA in 19 starts for Triple-A Memphis.
- Morris would have become the 39th active pitcher in the 100-win club.