Inmates Donnie Russell Row and Ricky Dubose are suspected of overpowering the guards while being transported by bus to another facility.
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 and secure the 31 other inmates that had also been aboard the bus.
The US Marshals Southeast Regional Fugitive Task Force, the FBI, and the Georgia Bureau of Investigation are investigating.
According to police, the incident occurred around 05:45 local time near the town of Eatonton.
Putnam County Sheriff Howard Sills said the inmates are "dangerous beyond description", adding that investigators are reviewing surveillance footage from on board the bus to determine how the inmates were able to attack the guards.
"They were inside the caged area of the bus," Sheriff Sills said at a press conference. "How they got through the locks and things up to that area I do not know."
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.
Correctional officers Christopher Monica, 42 and Curtis Billue, 58, were both killed, the Georgia Department of Corrections confirmed.
"Our hearts are heavy as we mourn the loss of two of our officers, who are our family, and our priority is to locate these fugitives and bring them to justice for this heinous act against those working to protect the public," said Corrections Commissioner Gregory Dozier.
"Obviously it's a tragic day for the family of corrections and the loved ones of these two officers. My heart is still in the soles of my shoes," Mr Dozier added.
The inmates are thought to be travelling in a 2004 green Honda Civic, which they carjacked.
They were armed with the officers' .40 calibre Glock pistols, officials say.
Nearly six hours after the escape, police in the city of Madison, Georgia, reported that a home had been broken into and clothing had been stolen.
The suspects left prison uniforms, and the stolen car has not yet been recovered.
Georgia Governor Nathan Deal said: "Our heartbreak is matched only in our resolve to bring their murderers to justice.
"No effort will be spared in pursuit of the killers, and no state resources required in this endeavor will be spared."
Both men had been serving life sentences.

Tomas Driukas, 26, from Birmingham, was jailed for life in 2016 for killing his daughter Deimante Driukaite.
An investigation found the baby died as a result of a brain trauma consistent with being shaken with force.
The NSPCC said the review highlighted that healthcare professionals "must leave no stone unturned when dealing with vulnerable families".
Police said Driukas had shaken his daughter because she would not stop crying.
Deimante died on 1 April 2015 in hospital after her father called an ambulance to the family home in Perry Barr, Birmingham.
The serious case review said Driukas and his partner were Lithuanians who had settled in England in 2010.
Its author Jim Stewart, an independent social work consultant, said the family had faced pressures related to Deimante being born prematurely and having complex health needs.
"They were young parents living in another country... clearly facing a challenge," he added.
"The family lived in a privately rented multiple-occupancy house and had limited extended family support."
Mr Stewart said the family's needs were not clearly understood by healthcare professionals.
"A significant opportunity was missed to explore the complex needs, [the] parents' capacity to meet their needs, cramped home conditions and for joint planning between hospital and community health professionals."
However, the report concluded Deimante's death could not have been prevented.
An NSPCC spokesperson said: "Deimante suffered horrifically at the hands of her own father, who carries sole responsibility for her violent and tragically early death.
"While Tomas Driukas's vile actions could not have been predicted, the review highlights that professionals in Birmingham and elsewhere must leave no stone unturned when dealing with vulnerable families with complex needs."
Two prison officers were shot and killed during an escape on Tuesday morning in the US state of Georgia.
[NEXT_CONCEPT]
A four-month-old baby's murder by her father could not have been predicted, a serious case review has found.