Piscotty's two-run homer in the top of the 11th off Cleveland's Josh Tomlin put Oakland ahead 5-3 and Blake Treinen (4-1, 0.80 ERA) shut the door in the bottom of the frame as the Athletics evened the weekend series with the Tribe at one game apiece.
The A's added a third run in the 11th on a Francisco Lindor error that allowed Matt Chapman to score from third base.
Tomlin (0-5, 6.99 ERA) took the loss after Cleveland's bullpen could not hold a three-run lead for starter Corey Kluber.
Oakland rallied from a three-run deficit in the eighth behind Lowry's two-run homer to right field off Indians reliever Neil Ramirez. Kris Davis followed with a solo blast to the bleachers in left that tied the score at 3-3.
The home runs marked the first earned runs allowed by Ramirez in his last 18 appearances, snapping a streak of 15 2/3 scoreless innings. They were also the first extra-base hits Ramirez surrendered in his last 13 innings.
Ramirez's stumble ruined an otherwise brilliant outing for Kluber who tossed seven shutout innings, scattering five hits and striking out three. It was his seventh quality start in seven outings against an American League West Division opponent.
Francisco Lindor made a diving catch of a Dustin Fowler line drive in the top of the ninth inning to preserve the tie with two out and the go-ahead run at second base.
Lindor led off the bottom of the first with a base hit and advanced to third on Michael Brantley's fourth double in his last three games. Lindor later scored on Edwin Encarnacion's RBI groundout to put the Indians in front 1-0.
It was Lindor's big-league best 79th run scored, the most by an Indians hitter through 87 team games since Kenny Lofton also had 79 at the same point in 1999.
Greg Allen made it 2-0 Tribe in the second with an RBI double over the head of Oakland's Stephen Piscotty to chase home Yan Gomes who had opened the inning by reaching base on an error.
Tyler Naquin singled and scored to make it 3-0 Indians in the sixth on Lindor's bloop single to right off Oakland's Ryan Buchter.
The Indians' home winning streak was not the only thing that did not survive Saturday's game. A television camera along the third base line was also among the casualties of the day.
Encarnacion ripped a foul line drive in the bottom of the fifth that smashed the front of the camera, rendering it useless for the remainder of the game.
According to StatCast, Jackson's two-seam fastball arrived at 93.1 mph and left Encarnacion's bat at 104.9 mph before obliterating the camera.
First and foremost
The Indians have scored 65 runs in the first inning, most in the American League and second in the majors (Colorado, 73). The club ranks third in baseball with 18 first-inning homers and fourth with a .276 batting average.
What it means
The loss snaps Cleveland's eight-game home winning streak, which was the longest since the club won 11 in a row from Aug. 24 through Sept. 14 of 2017 as part of their American League-record 22-game win streak.
Kluber threw 102 pitches, 63 (62 percent) for strikes. Jackson threw 98 pitches, 58 (59 percent) for strikes.
Thanks for coming
The Indians and Athletics drew 33,195 fans to Progressive Field on Saturday afternoon. First pitch was at 4:11 p.m. with a temperature of 77 degrees.
Right-hander Shane Bieber (4-0, 2.97) faces the Athletics on Sunday afternoon at 1:10 p.m. SportsTime Ohio, and WLKR/FM will carry the game. Lefty Brett Anderson (0-2, 7.63) gets the start for Oakland.