With the score tied at 6, Zobrist doubled to right field off Chris Ray to lead off the Rays' eighth.
"I'm just looking for a fastball there, a fastball to drive, really," Zobrist said. "It was away, and I just kind of got around it, pulled it into that right-center gap there. Hit it off the end a little bit, but enough to get it out there.
"And I think if I had read the throw a little better from right-center there, I could have gotten to third. But it was a hard read."
Zobrist advanced to third when the next hitter, B.J. Upton, grounded out to shortstop Cesar Izturis.
"I could tell that [Ray] was trying to stay with that slider against B.J.," Zobrist said. "So I'm just reading it off the bat. If it's a slow chopper or something like that, I'm going to try and make it to third if I can, so we have a better shot with one out over there. It worked out.
"I think if Izturis comes up and tries to make that play at third, it would have been a close play. Fortunately, he went to first with it."
Danys Baez entered the game to face Pat Burrell, who hit a pitch to center field that went deep enough to allow Zobrist to score the winning run from third.
In addition to scoring the winning run, Zobrist hit a home run in the first inning. He also started at first base, an unfamiliar position to him, and made a diving stab of a shot down the line by Brian Roberts to prevent extra bases. After moving to right field in the eighth, he robbed Ty Wigginton of a potential extra-base hit for the second out in the ninth.
"How about [Zobrist's] game? Let's think about all the things he did tonight," Rays manager Joe Maddon said. "He made the great play at first, great play in right field, great baserunning play. You're going to talk about the double, but advancing from second to third is absolutely, incredibly large. And that's what allowed us to score.
"You can't say enough about what he has done this year and how much he has grown as a player. He's playing as hard as if it was the first game of the season."
Zobrist's heroics in the eighth and ninth innings would not have been possible had Willy Aybar not come through as a pinch-hitter with two outs and two aboard in the seventh. The Rays trailed, 6-3, when the switch-hitting Aybar stepped to the plate to hit left-handed against Orioles right-hander Matt Albers. Facing a 2-2 count, Aybar sent a drive into the right-field stands to tie the game at 6.
"It has become a situation where no matter who you put in, no lead has been safe," Orioles manager Dave Trembley said. "What it's been is the third out. The third out has been elusive."
Lance Cormier finished out the eighth inning for the Rays and got the first two outs in the ninth before Roberts singled. Grant Balfour took over, and he retired Lou Montanez on a liner to Carl Crawford in left to preserve the win and earn his second save of the season.
The Rays took a 2-0 lead in the first inning on home runs by Gabe Kapler and Zobrist, which established a team record for homers in a single season with 191.
Jeff Niemann started for the Rays and never looked comfortable on the mound. During his 3 1/3-inning stint, he allowed four runs on seven hits, including a two-run homer by Roberts in the fourth.
"He was totally out of sync," Maddon said. "Nothing wanted to work. He just had no command today. I truly believe a large part of it is fatigue more than anything."
Evan Longoria hit his 32nd home run of the season on a 1-1 pitch from Mark Hendrickson in the fourth. His lined shot to the corner porch in left field cut the Orioles' lead to 4-3.
Jeff Fiorentino had an RBI single off Andy Sonnanstine in the fifth, and Melvin Mora added an RBI single in the sixth to push Baltimore's lead to 6-3.
"Right now, we're just trying to persevere to the end and keep playing hard and pull some wins out and finish with a winning record," Zobrist said. "Just finish the season well. We've played well at home. It was nice to come back yesterday on the road, but then to do the same thing at home, it definitely makes us feel good going into this last week. We want to finish strong really bad."