Richard Matt, 49, and David Sweat, 35, used power tools to cut through walls at the all-male Clinton Correctional Facility in the small town of Dannemora overnight Friday to Saturday in New York state.
They then crawled to freedom through tunnels, leaving behind a taunting note on a yellow Post-it saying "Have a Nice Day" next to a toothy grin.
Police backed by K-9 units and helicopters have scoured the area, and alerted officials on the Mexican and Canadian borders but there has been no trace of the two men. Police admit they could be anywhere.
New York Governor Andrew Cuomo said Monday that he believed they were assisted -- "probably from the inside."
"You have three types of employees at a prison. You have the guards, civilian employees and private contractors who come in to do work," he told NBC television on Monday.
"We are going through the civilian employees and the private contractors first. I would be shocked if a corrections guard was involved in this. But they definitely had (help) otherwise they couldn't have done this on their own."
US media reported that a female prison worker was questioned by police and removed from her post in connection with the investigation.
The New York Post said the worker may have been wooed by Matt, whom the paper described as "an infamous lady killer."
There is a $100,000 reward for information leading to their arrest and a new tip line for members of the public to call.
"They're dangerous wherever they are in the country," said Cuomo.
"Even from the equipment point of view. It took days to accomplish this. It really could have been a movie script," said Cuomo.
US media has compared it to Hollywood movies The Shawshank Redemption and Escape from Alcatraz.
The prisoners, who lived in adjoining cells, used power tools to drill through walls and pipes and left behind clothing in their beds as decoys to make it appear they were still in their cells, officials said.
Police with bulletproof vests and rifles manned roadblocks to and from Dannemora, a community of some 1,700 people located 170 miles (270 km) north of the state capital Albany.
No one had previously escaped from the maximum security portion of the prison, which the Village of Dannemora says opened in 1845.
About 3,000 inmates live at the prison, according to its website.
Matt and Sweat were found missing during a 5:30 am bed check on Saturday, according to state police.
After cutting through the steel back walls of their cells, they reportedly clambered along a six-foot (1.8-meter) high catwalk to access a twisting series of pipes and tunnels, through which they also cut their way.
They then made their way through the pipes and climbed up through a manhole onto a nearby street, The New York Post said.
Matt, who is six feet tall and has multiple tattoos -- including a Marine corps insignia on his right shoulder -- was serving a sentence of 25 years to life for kidnapping a man and beating him to death.
He also has tattoos on his back with the words "Mexico Forever."
Sweat, who has tattoos on his left bicep and his right fingers, was serving a sentence of life without parole for killing a sheriff's deputy. He shot the man 22 times, The New York Times reported.