Three state troopers were injured in the incident in Frankstown Township, about 100 miles east of Pittsburgh.
Investigators suspect the shooter might have been driving when he opened fire, shooting people for unknown reasons, the Pittsburgh Tribune Review reported, citing an official with the Blair County Emergency Management Agency.
"The Pennsylvania State Police have neutralized the active shooter in Frankstown Township, Blair County. There is no longer a threat to residents and visitors to this area from this individual," the Blair County Emergency Management Agency said on its Facebook page.
The shooting took place with much of the United States still highly sensitive to gun violence one week after a gunman killed 20 school children and six adults at an elementary school in Newtown, Connecticut.
Pennsylvania state trooper Adam Reed said the shooting was believed to take place between 9 a.m. and 9:30 a.m.At 9:30, Newtown held a moment of silence on Friday in remembrance of the children and teachers killed exactly one week ago in Connecticut. The National Rifle Association pro-gun lobby later issued a statement in response to the Newtown shooting, urging armed guards at the nation's schools.
Asked if the Pennsylvania shooting might have had any connection with the Newtown events, Reed said, "I don't believe it did, but that's all still being looked into."
The unidentified highway shooter killed two other men and a woman, the Altoona Mirror reported, citing the prosecutor, Blair County District Attorney Richard Consiglio.
One trooper was hit in his bulletproof vest and another was hit by flying glass when the shooter fired on his car, the Mirror said. The third trooper was injured in a crash involving the suspect, the newspaper reported, citing Consiglio.
Police said they would hold a news conference soon to release details.
(Reporting by Drew Singer and Daniel Trotta; Editing by Sandra Maler, Alden Bentley, Gary Hill)