The bus, with 21 passengers on board, had just arrived in Digos when the blast rocked the back portion of the vehicle, said bus conductor Mike Bangcot.
The explosion came two days after a bomb blast at a grocery store in Sulu killed five people and wounded 20 others.
Sulu authorities blamed the blast on suspected al-Qaeda-linked Abu Sayyaf rebels.
Chief Inspector Casar Cabuhat, Digos police chief, said 22 people were brought to a hospital with minor injuries, mostly from glass splinters.
"Our investigation is still ongoing and we cannot tell yet what type of explosive was used," Cabuhat said.
He said police were looking at all possible angles and had no suspects yet.
Witnesses said two young men boarded the bus in Midsayap, North Cotabato and alighted in Digos. Minutes later, the blast occurred reportedly near the area where they were seated.
The owner of the bus, the Weena bus company, had been the victim of extortion attempts by criminal gangs, but it was not immediately clear if the latest attack was linked to extortion.
Last March 10, a similar explosion targeted another Weena bus in Cotabato City, but there were no casualties.
The Weena bus firm plies between the cities of Davao and Cotabato.
Digos Mayor Arsenio Latasa tightened security in the city following the explosion.
Last March 13, a bomb was found inside a Bachelor Express bus bound for Bukidnon, causing panic at the Agora bus terminal in Cagayan de Oro City.
Police defused the bomb and also found maps of towns and cities in Mindanao, particularly those in Cotabato, Bukidnon and Misamis Oriental.
This prompted Chief Superintendent Geary Lingan Barias, Cagara police director, to direct the police chiefs of the cities of Butuan, Surigao and Bislig to conduct random checks of passenger buses on national highways and at transport terminals.
In 2002, explosions inside two buses in the cities of Butuan and Surigao left four people dead and several others wounded. The blasts occurred almost simultaneously.