The dead included women and children.
The Sunday evening blast occurred in Abbas Town, a Shiite Muslim neighborhood in the port city of Karachi, which has been plagued for months by such sectarian, political and gang violence.
Shiites, a minority in Sunni majority Pakistan, have been targeted in similar attacks lately in other cities of the country.
The Sunday attack came during evening prayer time. The blast occurred near a mosque and two apartment blocks, Dawn newspaper reported. The apartments suffered heavy damage and Dawn said there were reports several residents died inside their apartments, raising concerns more victims may be buried under the rubble.
Initial estimates said up to 50 apartments and at least 10 nearby shops were destroyed and more structures were damaged, many of them in resulting fires.
Karachi police official Aleem Jafri told Dawn an explosive-laden vehicle might have been used in the attack.
The explosion created a four-foot deep and 10-foot circumference crater at the site.
"About 45 deaths have occurred and as many as 135 wounded are in various hospitals," a provincial health official was quoted as saying. Karachi is the capital of Sindh province.
Rescue workers said some bodies were charred beyond recognition.
Several Shiite organizations called for a strike on Monday to register their protest. They also declared three days of mourning.
Some earlier reports said there were two explosions at the site. But they could not be confirmed.
"Why are we being targeted because of our beliefs?" one of the residents in the area told the Express Tribune. "Our only sin, our only fault, seems to be that we belong to a different sect."
No group had yet claimed responsibility for the attack.
Recent attacks on Shiites include two, one last month and the other in January, both in Quetta, capital of Balochistan province, which has a large population of the minority community called Hazaras. About 170 people died in those two attacks.
Shiites comprise about 20 percent of Pakistan's total population of 180 million.
Pakistani Prime Minister Raja Pervez Ashraf and President Asif Ali Zardari both immediately condemned the attack, CNN reported.
Also on Sunday near Karachi, unknown gunmen riding motorcycles shot and killed four policemen at a highway check post, Xinhua News Agency reported, quoting police. The attackers fled the scene after their late night attack. Other details were not immediately available.
Notable deaths of 2014 [PHOTOS]