Balochistan National Party (BNP) leader Malik Naveed Dehwar and his guard were killed when unidentified gunmen opened fire at the former's vehicle in Quetta's Arbab Karam Khan Road area on Thursday afternoon, police said.
Another man identified as Haji Essa was also injured in the attack.
The assailants escaped unhurt after spraying bullets at Dehwar's car, killing him on the spot. The injured were rushed to Quetta Civil Hospital's trauma centre for treatment.
Police and personnel of other law enforcement agencies reached the scene as an investigation into the incident was underway.
No group has claimed responsibility for the attack as yet.
Meanwhile, the BNP has strongly condemned the killing of its leader and urged the government to arrest the killers.
Malik Naveed Dehwar was a local leader of BNP, which is led by Sardar Akhtar Mengal, the former chief minister of Balochistan.
Chief Minister Balochistan Nawab Sanaullah Zehri also strongly condemned the incident and directed the police to arrest the culprits behind the killings.
The incident came hours after unidentified assailants attacked the convoy of Balochistan Health Minister Rehmat Saleh Baloch in Panjgur area, with the minister and his aides remaining unharmed in the incident.
Balochistan has been experiencing incidents of violence and targeted killings for over a decade.
The largest province of the country by area, it is home to a low-level insurgency by ethnic Baloch separatists. Al Qaeda-linked and sectarian militants also operate in the region. The province shares borders with Afghanistan and Iran.