Kipnis hit a two-run homer in the ninth inning off Nathan and the Indians snapped a five-game losing streak, beating the Texas Rangers 5-4 on Thursday night.
Nathan (2-4) had converted a club-record 31 straight save chances before the Indians erased a 4-2 deficit in the ninth. The right-hander's only other blown save this season came April 11 against Seattle.
"It's special any time you do it," Kipnis said. "You're in the big leagues. Everybody is a big name here."
The Cleveland second baseman lined a 1-0 pitch several rows deep into the seats in right.
After Kipnis' drive, Carlos Santana doubled to chase Nathan without him recording an out.
"I know my location was off," Nathan said of his pitch to Kipnis. "It was supposed to be down and away and I yanked one."
The Rangers remained three games ahead of Oakland in the AL West after the Athletics lost to the Los Angeles Angels.
Scott Maine (1-0) got the final two outs in the eighth in his third appearance with the Indians this season. Chris Perez pitched the ninth for his 36th save in 40 tries, helping Cleveland avoid a three-game sweep.
"It was a great team win," Indians first baseman Matt LaPorta said.
The Rangers scored twice to take a 4-2 lead in the eighth with the help of two errors.
Elvis Andrus reached on shortstop Brent Lillibridge's second throwing error of the game and scored when third baseman Jack Hannahan couldn't handle Nelson Cruz's grounder. Michael Young added an RBI single that gave the Rangers a two-run lead.
The Indians overcame three errors that led to three unearned runs.
"We tried to give it away," Cleveland manager Manny Acta said. "We didn't play very good defense. That was a great comeback against a guy like Joe Nathan."
Hamilton left Wednesday night in the eighth inning and received an injection after the game. Texas manager Ron Washington said he doesn't think it's a serious injury and Hamilton is expected to be back in the lineup Friday.
Adrian Beltre got two hits as the designated hitter, a day after leaving early with a left shoulder injury. Beltre was not in the original lineup before he convinced Washington that he was healthy enough to play.
LaPorta had three hits, including a two-run homer for the Indians, who are just 16-43 since the All-Star break.
The Indians completed a 10-game road trip with a 4-6 record.
"In the second half we've been struggling," Kipnis said. "To end a road trip with a win in the last game takes a lot of the pressure off. It's better than going back with our shoulders down and wondering why we lost another one."
Cleveland starter Zach McAllister allowed two runs and eight hits in six innings. The right-hander gave up seven runs over five innings in his previous start against the Rangers on Sept. 2.
Texas starter Derek Holland allowed seven hits and two runs. The Ohio native struck out seven and hasn't lost since July 31.
Beltre singled with one out in the fourth, Cruz doubled and Young followed with an RBI single. Cruz scored on Lillibridge's throwing error.
Vinny Rottino singled leading off the sixth and he came home on LaPorta's shot that made it 2-all. It was LaPorta's first home run of the season.
Acta said LHP David Huff will move into the starting rotation. Huff has pitched six scoreless innings in relief since being recalled from Triple-A Columbus on Sept. 4. He will take the place of Jeanmar Gomez, who is 5-8 with a 5.61 ERA. ... The Rangers reached 3 million in home attendance for the first time in club history. The crowd of 36,102 increased their season total to 3,003,143. Texas still has 10 home games remaining. ... Cleveland CF Michael Brantley (sore left pectoral muscle) was scratched from the lineup after taking batting practice, and SS Asdrubal Cabrera did not start for a fourth straight game with a sore right wrist. Cabrera, who entered as a defensive replacement in the ninth, will be examined when the team returns to Cleveland on Friday.