The Monday evening attack occurred during prayers at Mohallah Roshan Charagh in Topanwala bazaar in the Dera Ismail Khan region, the state-run Associated Press of Pakistan reported.
Police told news agency the blast was believed to have been set off by remote control. However, GEO TV quoted witnesses as saying an assailant riding a motorcycle hurled a hand grenade into the facility.
The BBC reported the blast destroyed the mosque's front wall and damaged its dome.
Dera Ismail Khan is about 186 miles from the provincial capital Peshawar. The region is near the tribal areas where pro-Taliban militants have been blamed for a spike in violence.
The BBC noted Shiites account for less 20 percent of Pakistan's predominantly Sunni population. Clashes between the two communities in the past decade have killed thousands of people.