Saqib Ismail Memon, a local police official in Shikarpur, told local media that the explosion occurred just before Friday prayers were due to begin, as a crowd was gathered outside the mosque, Al Jazeera reported.
The mosque is in the centre of Shikarpur city, which is home to about 150,000 people, around 500km north of the port city of Karachi.
The injured were taken to the nearby government-run civil hospital.
"Such attacks cannot lessen the spirit of the nation," said Interior Minister Chaudhry Nisar Ali Khan, in a statement released shortly after the explosion.
Friday's explosion is the second attack on a Shia mosque since Pakistani security forces stepped up operations against the Pakistani Taliban and its allies following a December attack on a Peshawar school.
In a previous attack, seven people were killed when a Shia mosque in the city of Rawalpindi was targeted in a suicide bombing on January 10.