The blast hit the mosque in Shikarpur in Sindh province, around 470 kilometres (300 miles) north of Karachi, as hundreds of worshippers attended Friday prayers.
Sindh health minister Jam Mehtab Daher told AFP that “a total of 40 have been killed in the attack, 46 others have been wounded”. Death toll was, however, feared to increase and it reached 55 around midnight.
Shaukat Ali Memon, the medical superintendent of Civil Hospital in Shikarpur, confirmed the death toll and warned it could rise further as many of the wounded were in a critical condition.
Hundreds of people rushed to the scene after the blast to try to dig out survivors trapped under the roof of the mosque, which collapsed in the explosion, witness Zahid Noon said.
Television footage of the aftermath showed chaotic rescue scenes as people piled the wounded into cars, motorbikes and rickshaws to take them for treatment.
“The area is scattered with blood and flesh and it smells of burnt meat, people are screaming at each other… it is chaos,” Noon told AFP.
“A huge contingent of police and rangers is present here and ambulances from the nearby towns have started to arrive.”
Local resident Mohammad Jehangir told AFP he had “felt the earth move beneath my feet” as he prayed at another mosque around 1.5 kilometres away.
An official with a national Shiite organisation, Rahat Kazmi, told AFP that up to 400 people were worshipping in the mosque when the blast struck.
Rising tide of violence
Abdul Quddus, a senior police official in Shikarpur, told AFP the initial investigation suggested it may have been a suicide attack.
It is the bloodiest single sectarian attack in Pakistan since March 2013, when a car bomb in a Shiite neighbourhood of Karachi killed 45.
Friday’s attack came as Prime Minister Nawaz Sharif visited Karachi, the capital of Sindh province, to discuss the law and order situation in the city.
Karachi, Pakistan’s biggest city and economic heart, has wrestled for several years with a bloody wave of criminal, sectarian and politician murders.
Anti-Shiite attacks have been increasing in recent years in Karachi and also in the southwestern city of Quetta, the northwestern area of Parachinar and the far northeastern town of Gilgit.
Around 1,000 Shiites have been killed in the past two years in Pakistan, with many of the attacks claimed by the hardline Lashkar-e-Jhangvi (LeJ).
A report by the US Institute of Peace this week warned that sectarian militant groups were growing in strength in rural areas of Sindh, a province which has escaped much of the worst of the violence that has wracked Pakistan over the last decade.
Pakistan has stepped up its fight against militants in the past month, following a Taliban massacre at a school in the northwestern city of Peshawar.
Heavily armed gunmen went from room to room at the army-run school murdering 150 people, most of them children, in an attack that horrified the world.
Since then, the government has ended a six-year moratorium on executions in terror-related cases and pledged to crack down on all militant groups.