Peralta's big shot off Pettitte (3-2) put the Indians ahead 4-3, and Franklin Gutierrez followed with a homer off the lefty.
Peralta had four RBIs and Jamey Carroll had a run-scoring single and stole two bases for the Indians, who scored all their runs with two outs.
Interim closer Rafael Betancourt worked a perfect ninth for his second save in two nights. He's filling in while Joe Borowski, last year's saves leader, rests a strained right triceps.
Jason Giambi homered twice and Hideki Matsui connected for the Yankees, whose previous trip to Cleveland ended with an unforgettable loss that began a chain of events leading to the end of manager Joe Torre's era in New York.
On an uncommonly warm Oct. 5 night, a swarm of midges off Lake Erie descended upon Cleveland's infield and seemed to enjoy feasting on then-rookie Yankees right-hander Joba Chamberlain during the eighth inning of Game 2.
Chamberlain's face and neck were covered with the tiny, flying critters, who bothered him so much that he uncorked two wild pitches, including one that allowed the Indians to tie a game they eventually won 2-1 in 11 innings.
The victory gave Cleveland a 2-0 lead in the best-of-five series, which they won in four. Torre was criticized for not taking his team off the field as the insects invaded and ended up turning down a one-year offer from owner George Steinbrenner before taking over the Los Angeles Dodgers.
Paul Byrd (1-2), who got the win when the Indians eliminated the Yankees in Game 4 at New York, allowed four runs and six hits in 5 2-3 innings. The right-hander gave up all three homers, but he didn't walk a batter and had his third straight strong outing.
Alex Rodriguez returned to New York's lineup and went 0-for-4. He missed three games with a strained quadriceps.
Down 3-1, the Indians scored four times with two outs in the fifth off Pettitte.
Travis Hafner singled to left and Victor Martinez followed with a base hit. Peralta, who came in batting just .184 (7-for-38) in his last 11 games, drove a 3-1 pitch over the 19-foot-high wall in left to make it 4-3. Gutierrez followed with his second homer - and first since his first at-bat this season - for a 5-3 lead.
Matsui brought the Yankees within a run in the sixth with his fourth homer, chasing Byrd. Rafael Perez came on and pitched 2 1-3 hitless innings.
The Indians made it 6-4 in the sixth off former teammate Billy Traber, again scoring with two outs.
Grady Sizemore walked, stole second and scored when Carroll dropped a soft single into left.
Giambi's second homer off Byrd gave the Yankees a 3-1 lead in the fourth.
Jorge Posada singled with two outs and Giambi crushed Byrd's pitch, driving it an estimated 455 feet into the right-field bleachers. Giambi has 36 multihomer games and his swing seems suited for Cleveland. He has homered in five straight games here and in seven of his last eight in the Indians' park.
Pettitte started last October's infamous bugfest, working 6 1-3 scoreless innings and dueling almost pitch for pitch with Fausto Carmona before the midges moved in.
Cleveland picked up an earned run in the first against him.
Sizemore reached on Giambi's error, Carroll got on with a fielder's choice and stole second, and after Pettitte walked Victor Martinez, Peralta singled in Carroll.
Giambi atoned for his miscue in the second with a 428-foot shot into the Indians bullpen.
