The fired officers include Michael Brelo, a patrolman cleared of manslaughter charges over the incident last year.
Six other officers are facing suspensions ranging from 21 to 30 days.
The shooting followed a high-speed chase that involved 62 police cars and more than 100 officers.
Steve Loomis, president of the city's largest police union, said he would contest the firings and suspensions.
"This is unprecedented... it's absolutely politically motivated," said Mr Loomis. "This discipline is not supported by fact."
The incident began with the sound of a small car in poor repair backfiring, which was mistaken for the sound of gunfire.
It ended with the death of Timothy Russell, who was shot 24 times, and Malissa Williams, who was shot 23 times.
Several officers fired, but only Officer Brelo faced charges. He stood on the car's bonnet and fired 15 shots through the windscreen in 7.4 seconds.
He was cleared of the charges in May of last year, after a judge said that he could not be certain that Mr Brelo was responsible for the deaths.
Police officials in Cleveland, Ohio, have fired six police officers who shot more than 100 rounds into car and killed an unarmed black couple in 2012.