"Khan was going to his office from home when four people on two motorbikes lay in wait on both sides of the road," police official Imran Shahid said.
"They opened fire on his vehicle. His bodyguard and his driver have been killed," Shahid told AFP.
A spokesman for the Lady Reading Hospital said the commander was in a critical condition.
"We have received two dead bodies and the situation of the deputy commander is critical. He has been hit by three bullets and he is in surgery," the spokesman, Jamil Shah, told AFP.
There was no immediate claim of responsibility.
The attack came hours after suicide gunmen and car bombers targeted an office of ISI in Sukkur, sparking a shootout that left seven people dead.
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So TTP supporters .. is this the Naya Pakistan that we were promised in 90 days ... only a few weeks left to straighten up the mess.