The announcement by athletic director Pat Haden was made on the school's website early Sunday. This follows USC's 62-41 defeat at Arizona State on Saturday which equals the most points scored against USC in school history.
Kiffin reportedly learned of his termination as the team returned to Los Angeles.
USC athletic director Pat Haden officially named Ed Orgeron the interim head football coach during a news conference Sunday.
USC has lost seven of its last 11 games. The Trojans are 0-2 in the PAC-12 and 3-2 overall this season.
Kiffin's overall record in four seasons with the Trojans is 28-15.
It has been rough for Kiffin from the beginning. Just months after the 38-year-old became coach at USC, the Trojans were hit with severe NCAA sanctions. That included a two-year bowl ban and the loss of 30 scholarships over three years.
Kiffin had nothing to do with the wrongdoing, but it set the stage for a bumpy ride.
The news comes less than five months after Haden said his head coach was as good as he could be in the face of the sanctions. Before the season began, Haden said he was 100 percent behind Kiffen.
The decision is not a big surprise to people, and most are happy with the news. Eyewitness News viewers on Facebook voiced their opinions.
"Finally, SC wakes up and smells the coffee. Maybe they finally realized they won't be smelling the roses again with Kiffin," said Brent Collins.
USC's next game is Oct. 10 against the University of Arizona, giving the team about a week to figure out the coaching situation.
On Sunday, USC players took to Twitter to express their opinion of Kiffin's sudden firing.
USC player Marcus Martin tweeted "Clean slate ! Lets get after it trojan family, still got a great season ahead of us #FightOn".
Nelson Agholor tweeted "No coach will ever tackle,catch , block or throw for you ... I hope everyone on my team agrees."
ESPN is reporting Denver Broncos defensive coordinator Jack Del Rio is a possible candidate to replace Kiffin. Multiple team sources told ESPN, however, that Del Rio will stay through the Broncos season even if he takes a new job for the 2014 season.
The Associated Press and City News Service contributed to this report.