The new route, which operates five times a week, is the first direct link between the two cities and allows passengers travelling from the West Midlands to board onward flights to destinations such as Chicago, Las Vegas and San Francisco.
Chief executive of Birmingham International Airport Paul Kehoe was present to welcome passengers travelling on the inaugural flight yesterday (May 13th).
"Having US Airways as one of our partners is excellent news, not just for the airport but also for the region," he commented.
"It is encouraging that the outbound flight this morning is over 70 percent full which is excellent for an inaugural."
Flights will land in Birmingham at 06:25 BST, with the return flight taking off at 08:45 and arriving back in Philadelphia at 11:50 (local time).
Cheap flights carrier bmibaby recently launched its 2009/10 winter schedule from the airport, which includes flights to Grenoble, Amsterdam and Malaga.