Police were trying to determine whether the blast, which reduced the bus to a charred skeleton, was caused by a bomb or a gas canister that exploded, said police spokesman Imran Shaukat. Many buses in Pakistan run on natural gas.
Karachi has a long history of political, ethnic and sectarian violence. It is also believed to be home to many Taliban militants who have fled U.S. drone attacks and Pakistani army operations in the country's northwest.
Associated Press writer Adil Jawad in Karachi, Pakistan, contributed to this report.