After several years of lobbying government agencies and fighting legal challenges from other airlines, Piedmont received authorization on January 1, 1948.

Its early routes stretched from Wilmington, North Carolina, northwest to Cincinnati, Ohio, with intermediate stops.

"[9] Piedmont's first jet flights took off in March 1967: 92-seat Boeing 727-100s on such routes as Atlanta - Asheville - Winston-Salem - Roanoke - New York LaGuardia Airport.

The map reached Knoxville in 1951–1952, Columbus OH and Washington DC in 1955, Atlanta and Baltimore in 1962, New York La Guardia in 1966, Nashville and Memphis in 1968 and Chicago Midway in December 1969.

[14] After deregulation in the late 1970s the airline grew rapidly and developed a hub at Charlotte/Douglas International Airport in Charlotte, North Carolina.

Piedmont bought Empire Airlines, based in Utica, New York, in 1985 which brought more Fokker F28 Fellowships into the fleet.

New Boeing 767-200ERs (ER for "Extended Range"), the airline's only wide-body jet, flew nonstop Charlotte to London Gatwick Airport beginning in 1987.

[15] Shortly before it was acquired by USAir, Piedmont was the first airline to announce fleet-wide adoption of the Traffic Collision Avoidance System (TCAS).

[18] Piedmont's expanding route system, its loyal passenger following, and its profitability caused it to gain notice among other airlines for a potential buyout.

On October 30, 1959, Piedmont suffered its first crash when Flight 349 slammed into Bucks Elbow Mountain near Charlottesville, Virginia due to a navigational error, whose cause remains in dispute.

On July 19, 1967, Piedmont suffered another fatal accident when Flight 22, a Boeing 727-100, collided with a Cessna 310 over Hendersonville, North Carolina.

The National Transportation Safety Board (NTSB) found that the probable cause was "an unrecognized loss of altitude orientation during the final portion of an approach into a shallow, dense fog.

The disorientation was caused by a rapid reduction in the ground guidance segment available to the pilot at a point beyond which a go-around could not be successfully effected.