Rashid Godil, 54, was on his way home with his wife when armed men on two motorcycles attacked his vehicle and fired eight 9mm bullets after identifying the Muttahida leader.
Godil's driver was killed and the Muttahida Qaumi Movement leader was critically wounded, said Abid Qaimkhani, a senior police officer.
Godil was rushed to a nearby hospital where he underwent surgery following which the he was put on ventilator, according to hospital sources.
The attack on Godal comes just two days after Punjab interior minister, Colonel (retd) Shuja Khanzada was killed in a bomb attack at his office in Attock.
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Godil had served as MQM's deputy parliamentary leader in the National Assembly until MQM lawmakers' recent submission of resignations to protest against an alleged military crackdown against the party and its supporters in Karachi.
The attack took place while head of Jamiat Ulema-e-Islam party Maulana Fazlur Rehman was visiting the party headquarters to hold talks with a Muttahida delegation over the issue of MQM legislators' resignations.
Prime Minister Nawaz Sharif, in a statement, also condemned the attack on Godil and prayed for his recovery.
The situation in many parts of Karachi was very tense as many markets, shopping centres and petrol pumps started to close down out of fear.
MQM, Karachi's largest party and a dominant force in Sindh, claims to represent the Urdu-speaking population that migrated from India after partition.
The party complains against the Sindh government for failing to set up committees to monitor the Karachi operation, launched in September 2013 to bring peace in the city of over 18 million.