Scherzer allowed four runs, two of which scored on his throwing error, as the Cardinals drove another nail in the D-backs' playoff coffin with a 4-2 win.
The D-backs trail the first-place Dodgers, who won on Wednesday, by four games in the National League West with just four games to play.
"This time in the season it really hurts," said Scherzer, who fell to 0-4. "We really needed a win tonight."
Scherzer didn't seem to have his best stuff in the first inning when he allowed three baserunners, but he managed to pitch out of the jam without any damage.
He wasn't so fortunate in the second. After allowing a leadoff single and a walk, Scherzer fielded a bunt by pitcher Adam Wainwright and threw past second baseman David Eckstein, who was covering first. Both runners came home on the play.
"I slowed down a little bit, and it sailed out of my hand enough for Eckstein not to be able to make a great play on it," Scherzer said.
"It took off, yeah," Eckstein said. "Hit off the end of my glove. It's one of those things."
The D-backs tied the game in the third when Chris Young singled home Scherzer, and Conor Jackson drove in another on a double-play groundout.
It didn't stay that way for long, though, as another one of "those things" hurt the D-backs.
This time, it was third baseman Mark Reynolds, who misplayed a grounder to lead off the fourth. Josh Phelps reached on the miscue, and he came around to score later in the inning, as the Cardinals took the lead for good.
"Just a topspin chopper," said Reynolds. "He hit it hard, and it hit off my wrist. I've done it 30 other times this year."
It was a tough night for Reynolds, who tied Ryan Howard's Major League single-season strikeout mark of 199 in the second. The error was Reynolds' Major League high 34th.
Of the four St. Louis runs on the night, just two were earned.
"That was the key, the defensive miscues," D-backs manager Bob Melvin said. "They capitalized on every one of them. It's a different game if we field the ball cleanly, throw the ball and catch the ball."
It also may have resulted in a different result for Scherzer, a St. Louis native, who had over 60 friends and family in attendance for his first big league game here. The rookie right-hander wound up allowing seven hits over his five innings.
"It was fastball command," Scherzer said when asked what caused him problems. "I had a slider, and I was able to locate that down and in how I'd like to. I was able to throw my changeup. But working my fastball in and out, I didn't have too much command on it early in the game."
"I thought he threw the ball reasonably well," Melvin said. "It probably wasn't his best fastball that we've seen."
A lifelong Cardinals fan, Scherzer talked early in the week about how excited he was to get an opportunity to pitch at Busch Stadium. He received plenty of calls and text messages this week, but said his below-standards performance had nothing to do with being overwhelmed by the moment.
"As soon as I got to the clubhouse today, all the surrounding stuff went away," he said. "As soon as I started stretching, it was all about pitching, nothing more than that. It's all about baseball, then. I've pitched in big games all of my life, and I know how to handle that. You go out there and slow the game down and go right after them."
Steve Gilbert is a reporter for MLB.com. This story was not subject to the approval of Major League Baseball or its clubs.