Holliday was 0-for-2 with a strikeout against rookie right-hander Kyle Hendricks before elevating a 2-2 sinker squarely to left-center that tied the game at 3 in the sixth.
"Down early, having trouble really putting anything together against Hendricks, then Matt comes up in a big situation and makes something happen," manager Mike Matheny said.
Holliday drew an eye-level sinker, high and in on the second pitch of the at-bat before blasting the homer three pitches later. The Cubs went to the bullpen just after Holliday smacked his second homer in seven at-bats against Hendricks, and sixth against Chicago this year.
"They come way up and in on a pitch, too, that I hate to see happen -- our guys, their guys, anybody," Matheny said. "That was up close. Sometimes that just brings enough out of the guy that the next thing you know, you're watching one land in the seats. I was real happy to watch that."
"I was trying to pitch around him," Hendricks said. "If I walk him, I walk him. I know that, that's my mindset, and we talked about that in the [pregame] meeting. I throw a sinker, it starts on the black and cuts -- it didn't sink. I went back and watched it on video, and I still can't believe it ended up where it did. You just have to move on, and thank God we won."
Holliday has amassed 271 homers in his 11-year career, 16th among players on an active big league roster and not suspended. Of those ahead of Holliday, only Miguel Cabrera and David Ortiz have at least 20 homers in each of the last nine seasons.
The long ball was Holliday's third this year and seventh overall at the Friendly Confines, third most of any park that he hasn't called home.
The veteran left fielder is a career .308/.385/.523 hitter, with 1,056 RBIs and experience in 59 postseason games. Holliday's high mark for homers in a season is 36, set in 2007 with the Rockies.
Daniel Kramer is an associate reporter for MLB.com.