The decision comes just two days after the Trojans, who entered the season with aspirations for a Pac-12 Conference championship, suffered a 42-28 home loss to Stanford.
"As I committed to upon my arrival at USC, during the past two off-seasons we provided every resource necessary for our football program to compete for championships," Bohn said in a statement. "The added resources carried significantly increased expectations for our team's performance, and it is already evident that, despite the enhancements, those expectations would not be met without a change in leadership."
Donte Williams will serve as the Trojans' interim head coach, according to the school. He joined USC's coaching staff in 2020 as the cornerbacks coach and defensive pass game coordinator before he was promoted to associate head coach after last season.
Helton had been with the program since 2010, when he was hired to be the Trojans' quarterbacks coach on Lane Kiffin's first staff. He served as offensive coordinator under both Kiffin and Steve Sarkisian before being hired as head coach by then-athletic director Pat Haden in 2015.
The 49-year-old Helton posted a 46-24 record as USC's head coach. He had a 2-3 mark in bowl games, including a Rose Bowl victory to conclude the 2016 season.
USC went 1-1 under Helton to begin this season.
"I want to be exceptionally clear: our university and its leadership are committed to winning national championships and restoring USC football to glory," Bohn said. "This decision represents our next step toward that goal in what has been a thoughtful and strategic process to build a comprehensive football organization equivalent to the premier programs in the modern landscape."
Bohn said a national search for Helton's replacement will take place over the next several months.