Inmates Donnie Russell Row and Ricky Dubose are suspected of overpowering the guards while being transported by bus to a work assignment.
Police say the men, who are both serving time for armed robbery at Baldwin State Prison, hijacked the prison transport bus.
They later commandeered another car, and are considered armed and dangerous.
The first call to police came shortly after 07:00 local time (11:00 GMT), once the men had apparently taken control of the prison bus on Highway 16 between the towns of Sparta and Eatonton.
Officials have shut down roadways in the region, about 65 miles (104km) from Atlanta, to conduct a search.
The US Marshals Southeast Regional Fugitive Task Force and the Georgia Bureau of Investigation are investigating.
According to police, the incident occurred around 05:45 local time near the town of Eatonton.
The prisoners "overpowered" the guards and "they then disarmed them and one of the subjects shot and killed both guards", according to a bulletin issued by the Putnam County Sheriff's office.
They are thought to be travelling in a 2004 green Honda Civic and armed with the officers' .40 calibre Glock pistols, officials say.
Both men had been serving life sentences.