Three motorcycle-borne assailants shot Baloch outside his home on Sariab Road in the morning, deputy inspector general of police Hamid Shakil told reporters.
Witnesses said Baloch, a former member of the senate or upper house of parliament and secretary general of the Balochistan National Party (Mengal group), was shot when he came out of the house.
Baloch was rushed to a nearby hospital where he succumbed to his injuries, doctors said.
The gunmen fled after the incident, the police said.
No group claimed responsibility for the attack.
The police said the assassination might be the latest in a series of targetted killings that has rocked Quetta, the capital of Balochistan province, over the past two years.
BNP activists organised protests in Quetta and other parts of Balochistan on learning of Baloch's killing.
Angry protesters blocked Jinnah Road, the main thoroughfare in Quetta, by burning tyres and forcibly closed shops and business establishments across the city.
There were reports of protests in several other cities, including Turbat, Mastung, Qalat, Hub, Bela and Khuzdar. Authorities closed Balochistan University for two days as a precautionary measure.
The police and paramilitary forces were put on alert in sensitive areas following the protests, officials said.
A large number of BNP workers and Baloch's relatives rushed to the civil hospital where he died. Footage on television showed them weeping near his body.
Baloch was elected a member of the Senate in 1997. He served as a member of several parliamentary standing committees.
A lawyer by profession, Baloch had studied in Russia and backed a peaceful struggle for the rights of the Baloch people. He started his political career during his days as a student.
He was highly respected by the political leadership of Pakistan and the people in Balochistan.
Baloch's BNP party says it believes in a peaceful and democratic struggle for the people of Balochistan to attain the right of self-determination.
