Mufti Nizam al-Din Shamzai, who called for a "jihad" against the US after the invasions of Afghanistan and Iraq and his three sons were wounded on Sunday outside the mosque he oversaw, said police official Fayiz Qurashi.
Shamzai's bodyguard returned fire and wounded one of the six attackers, Qurashi said, quoting witnesses.
"He has expired," said a source at the hospital to which Shamzai and his sons were taken.
"We have not yet announced it because there is a huge mob outside and we are worried about a law-and-order situation," he added, asking not to be named.
It was not immediately clear who was behind the attack or whether it was a sectarian killing.
A witness told Reuters at least four men opened fire as Shamzai, one of the country's most revered Sunni clerics, headed for his seminary from his nearby home accompanied by his sons, a bodyguard, a driver and one relative.
Shamzai's murder will likely spark
protests throughout Karachi
The private Geo television channel said the attackers made their escape by car and motorcycle.
Shamzai belonged to the hardline Deobandi school of Islamic thought, which has provided thousands of fighters to the Taliban in neighbouring Afghanistan.
His seminary, known as Banuri Town, taught many students who later became important members of the Taliban regime in Kabul.
Supporters of Shamzai went on the rampage at the news of the killing, attacking a police station in the Jamshed Quarters neighbourhood, torching vehicles and snatching rifles from constables.
Two protestors were injured when police opened fire. Eight policemen were hurt by stones thrown at them by the mob, while another three were injured in the attack on the police station, police said.
"The places of worship including Shia mosques are being guarded, we may call in army in case the situation gets out of
Aftab Shaikh ,
"Three policemen were injured when an angry mob ransacked the police station and some two to four prisoners also managed to escape from the lock-up," local police official Shah Ibne Masih told reporters.
The rioters also fired at a nearby bank, he said.
Some 15,000 paramilitary soldiers and police were deployed
around the city to prevent further violence, government advisor Aftab Shaikh told reporters.
"The places of worship including Shia mosques are being
guarded, we may call in army in case the situation gets out of
control," said Shaikh.
Fears of revenge
There were fears Sunni Muslims could attack members of the
minority Shia community in revenge. Rival Sunni and Shia fanatics have been killing the followers of each others' communities for some two decades in Pakistan.
Police said a mob tried to attack a Shia mosque on MA Jinnah road, near the scene of killing, but turned away when police started shooting and released tear gas.
The rioters later ransacked shops outside the tomb of the
founder of Pakistan, Muhammad Ali Jinnah, and ransacked the nearby Quaid-i-Azam Academy which keeps documents of Jinnah's.