Mackanin will remain with the organization, however, as the Phillies announced he agreed to an extension to become a special assistant to the general manager.
The Phillies entered play Friday with a 64-95 record this season, and they are just 172-237 in two-plus seasons under Mackanin.
Philadelphia made the decision to move forward with a different manager in 2018 despite signing Mackanin to an extension through 2018 in May, which included a club option for 2019.
Mackanin was named the Phillies' manager during the 2015 season after Ryne Sandberg stepped down.
Philadelphia closed out that season with a respectable 37-51 record under Mackanin, and went 71-91 last season in the midst of a rebuild.
The team took a step back this season from a wins and losses perspective, although they weren't expected to be anywhere near the playoff mix as they continue to develop their young players.
Philadelphia will hire its fourth manager since 2013 to succeed Mackanin, and it remains in search of its first playoff berth since the 2011 campaign.