Police had cordoned off the shrine of Lal Shahbaz Qalandar, a 13th century Muslim saint, early Friday as forensic investigators reached the town of Sehwan in Sindh province, some 200 kilometres (124 miles) northeast of financial hub Karachi.
The centuries-old shrine's white floor was still smeared with blood, with scattered debris including shoes, shawls, and baby bottles. At least 20 children are believed to be among the dead, the head of Sehwan's medical facility Moeen Uddin Siddiqui said.
At 3.30 am the shrine's caretaker stood among the carnage and defiantly rang its bell, a daily ritual that he vowed to continue, telling AFP he will "not bow down to terrorists".
The Islamic State group (IS) has claimed the attack, which came after a series of bloody extremist assaults this week, including a powerful Taliban suicide bomb in the eastern city of Lahore which killed 13 people and wounded dozens.
The attacks have dented growing optimism in security after Pakistan's decade-long war on militancy.
Military spokesman Asif Ghafoor said the attacks had been carried out from sanctuaries in Afghanistan and that Kabul had been asked to take action.
He also said the military had "closed" the porous border between the two countries, where Kabul and Islamabad have long accused each other of harbouring extremists.
"Scores of suspects have been arrested from different cities" in a pre-dawn crackdown, a government official speaking anonymously told AFP.
Security officials said at least 18 terrorists had been killed in Sindh province overnight, and 13 more in the country's northwest.
The Sindh provincial government announced three days of mourning as Pakistanis vented their grief and fury on social media.
"Sunnis, Shias, Hindus, ppl from all faiths visit Sehwan often to pay homage to the great saint. This is an attack on our identity amp; culture," said Twitter user Zahraa Saifullah.
Sufism, a mystic Islamic order that believes in living saints, worships through music and is viewed as heretical by some hardline groups.
The Sunni jihadist IS group has targeted Sufi shrines in Pakistan previously, killing more than 50 at a shrine in Balochistan province last year.