The 66-year-old Piniella announced before the game that he leaving to be with his ailing mother. Third base coach Mike Quade was promoted to interim manager.
The disappointing Cubs weren't able to send Piniella out as a winner. Omar Infante and Jason Heyward each hit a pair of home runs, and the Braves scored 11 times in the last three innings to break away.
Piniella was in the dugout when the game was over, and he waved his hat to longtime Braves manager Bobby Cox across the field. Cox plans to retire after the season.
Piniella hugged Cubs third baseman Aramis Ramirez before heading down the dugout tunnel to the clubhouse.
After contemplating the decision for several days and discussing it with Cubs general manager Jim Hendry, Piniella decided to walk away from baseball after 48 years as a player, manager and executive.
The surprising announcement came in a team handout in the morning, and after Piniella had repeatedly insisted he would finish the season.
"My mom needs me home and that's where I'm going," Piniella said.
The loss left the Cubs at 51-74. Atlanta held its lead in the NL East.
Piniella and Cox were honored before the game as they exchanged lineup cards at home plate.
Piniella and the umpiring crew posed for a picture. He shook hands with Cox, and they hugged each other and exchanged back slaps as Piniella's No. 41 was posted on the center-field scoreboard.
Cox made his last trip as a manager to Wrigley Field. He was announced to the crowd and took his cap off and waved it to the fans.
Braves starter Mike Minor (2-0) set a team rookie record by striking 12 in six innings. The lefty allowed three runs and six hits.
Heyward and Infante each finished with four hits, drove in four runs and scored four times. It was 5-3 before the Braves scored four runs in the seventh, five more in the eighth and twice in the ninth.
The Cubs have lost six of their last seven. Randy Wells (5-12) took the loss.
Rookie Cubs shortstop Starlin Castro finished 4 for 5 with two doubles.
NOTES: The teams each had 13 hits despite the lopsided final score. ... The Cubs have lost 12 of their last 14 at Wrigley.