The 66-year-old Piniella made the announcement in a release handed out by the team. Third base coach Mike Quade was promoted to interim manager.
Piniella said last month he planned to retire at the end of the season and reiterated his plans just Saturday. But he missed four games in August to be with his ailing mom in Florida and it appears he felt he needed to spend more time with her.
"I need to be home," Piniella said before Saturday's 5-4 victory over Atlanta. "My circumstances have changed a heck of a lot the last year, especially the last month or so. I just need to be home.
"I'm concerned about my mom. I love baseball but I love my family. When you talk about your family, it's a little more important than baseball, it's a lot more important."
Piniella's record with the Cubs was 316-292. Under the mellowed skipper, Chicago won consecutive NL Central titles in 2007-08, but missed the playoffs last year and has struggled again this season with a new owner in charge.
In 18 years in the majors as a player and another 22 as a manager, Piniella made five trips to the World Series and has three championship rings.
Piniella began managing in 1986 with the Yankees and lasted three years, including a stint as general manager. He managed the Reds from 1990-92, leading them to a World Series championship in his first season. He also got national attention during his time there for a clubhouse wrestling match with reliever Rob Dibble, who downplayed the incident and said "we've been family ever since."
After Cincinnati, Piniella had a long run in Seattle, where his teams won at least 90 games four times and 116 in 2001. The three-time manager of the year also spent three seasons in Tampa Bay's dugout.