Renfroe's slam pushed the Padres over the Cubs 5-2 on Monday, handing Chicago its fourth straight loss.
As big as that hit was, both teams marveled at how the Cubs had only three hits yet drew 10 walks and had two batters hit by pitches.
"It was enough from an offensive standpoint to overcome what should have been probably a disaster pitching-wise," San Diego manager Andy Green said. "You get to 12 free passes, 10 walks, two hit batters, you don't win baseball games like that. It's an aberration. It's not going to be a successful formula to winning more baseball games."
The defending World Series champion Cubs have lost six straight road games. They were coming off a three-game sweep at the Los Angeles Dodgers.
Said Cubs skipper Joe Maddon: "We had about 11 or 12 left on base and only three hits. That's the real tale of the tape, more so than Kyle's performance. We just have to be more efficient. We need to hit like we're capable of."
Hendricks (4-3) retired his first 10 batters before allowing seven of his final 11 to reach.
With one out in the fourth, Hendricks gave up singles to Yangervis Solarte and Wil Myers, and hit Ryan Schimpf with a pitch before Renfroe drove a 1-1 pitch into the seats in left. It was Renfroe's 10th this season and his second career grand slam.
"There were a lot of Cubs fans there and they were rooting on their team and it was loud," Renfroe said. "Obviously it quieted down real quick and Padres fans started picking up a little bit. You always want to quiet the crowd as much as possible and when you're doing that, obviously you're doing well."
Renfroe hit an inside pitch that probably was a ball. "It was the same pitch they threw me the first at-bat. I was late on the first one. I waited too long. I figured he'd come back there eventually and I got that pitch."
Renfroe's other slam was in his sixth major league game, against the Dodgers on Sept. 27, when he hit two homers and drove in seven runs. He hit four homers and drove in 14 runs in 11 games after he was called up.
Hendricks loaded the bases with no outs in the fifth and Myers drove in a run on a fielder's choice.
Hendricks was charged with five runs and six hits in five innings, struck out five and walked none.
Cosart lasted only four innings, giving up two runs, three hits and five walks and striking out two.
Maddon said the Cubs are trying too hard.
"It's not complicated," he said. "You can see the big swings coming out of our zone when just a single would do. We did it before, we can do it again. Everybody loved us a couple days ago, and now all of a sudden we've had a tough time scoring runs on the road and we've just got to do better. That's all it comes down to."
Cubs: RHP Eddie Butler (2-0, 1.93) is scheduled to start Tuesday night. He's 0-2 with a 5.68 ERA inn in three appearances against San Diego, including two starts. All three appearances have been at Petco Park.
Padres: Rookie RHP Dinelson Lamet (1-0, 1.80) tries to follow up on his brilliant big league debut, when he struck out eight in five innings while allowing one run on three hits in a 4-3 win at the New York Mets on Thursday.
More AP baseball: https://apnews.com/tag/MLBbaseball