Cpl. John Michener with Lancaster County's Southern Regional Police Department said the man didn't appear to be speeding and that it "doesn't appear there was anything on his part that caused the accident."
Police said the man was driving on a highway south of Lancaster when his vehicle struck the mules, crossed into the oncoming lane and then collided with the other vehicles.
The Intelligencer Journal/Lancaster New Era reported that drivers of both other vehicles required hospital treatment for minor injuries.
The coroner identified the driver who was killed as Melvin Ault, of East Petersburg, and attributed his death to multiple traumatic injuries, the newspaper reported.
Michener said Ault was meeting a family member to go hunting on the first day of Pennsylvania's primary deer-hunting season.
One mule was killed by the crash, while the other had to be euthanized. Michener said witnesses reported seeing four mules in all, but the other two were not immediately located.
Officer Jesse Blank told the newspaper the farmer did not realize that the mules had gotten out of the pasture.
"He said he changed their pastures yesterday," Blank said. "The portable electric fencing was juiced and working. It is unknown if a deer ran through it, or the animals themselves."
The crashes occurred before 6 a.m. on Route 272 near the village of Willow Street, some five miles south of Lancaster.