The blast badly damaged two five-story residential buildings on Sunday in the Abbas town area, setting one on fire, but police said the target of the attack was not yet clear.
Karachi is plagued by political violence, with more than 2,200 people killed in shootings and bombings last year, but major bomb blasts are relatively rare.
"At least 30 people were killed in this bomb blast, three of them were policemen," Fayaz Lughari, police chief of Sindh province said, warning that the death toll could rise. More than 50 people were injured.