The four gunmen approached the bus of Shiite Muslims while riding on motorbikes, armed with automatic weapons.
It is the second major attack in the insurgency-torn area in two weeks, AFP reports.
The bus was travelling to fruit and vegetable markets and was near the city of Quetta, the capital of oil and gas-rich Baluchistan, which borders Iran and Afghanistan, ABC reports.
Most of the victims were Shiite Muslims from the Hazara ethnic group, it reports.
"Four gunmen riding two motorcycles opened fire on a bus in the outskirts of Quetta," local police official Hamid Shakeel said.
"The death toll has risen to 13. Two of the injured who were in critical condition died in hospital. Now 12 Shiite Muslims and one Pashtun have been killed in the attack," he said after initially putting the death toll at 10.
Television footage showed the bus engulfed in flames, with luggage strewn across the ground.
Police sealed off the site of the attack as 400 furious Hazaras demonstrated outside the Bolan Medical Complex where the wounded were taken for treatment, condemning the government for inaction over sectarian groups.
Last month, gunmen attacked a bus carrying Shia pilgrims in a neighbouring district killing 26 people.
It was the deadliest attack on Shiites in Pakistan since September 4, 2010 when a suicide bomber killed at least 57 people at a rally in Quetta.
Gunmen then killed another three Shiites on the outskirts of the city who were going to collect relatives who died in the first incident.
Shiite Hazaras have been targeted in several killings by sectarian and criminal groups, according to human rights group Amnesty International.
"These are not random killings but demonstrate the deliberate targeting of the Shia by armed groups," said Amnesty's Asia-Pacific director Sam Zarifi.
"These attacks prove that without an urgent and comprehensive government response, no place is safe for the Shia."
Baluchistan has become an increasing flashpoint for sectarian violence between Pakistan's majority Sunni Muslims and minority Shiites, who account for around a fifth of the country's 167 million population, AFP reports.
On September 20, gunmen killed 26 Shiite pilgrims after ordering them off their bus in Mastung, a district 30 miles south of Quetta.