The province has been the scene of a long-running insurgency, with an array of separatist groups staging attacks, including the outlawed Balochistan Liberation Army, or BLA, designated a terror group by the United States in 2019.
A local deputy commissioner, Yasir Iqbal, said the attack took place on Wednesday on the outskirts of the city of Khuduzar as the bus was transporting children to their military-run school.
Troops quickly arrived at the scene and cordoned off the area while ambulances transported the victims to hospitals in the city.
No group immediately claimed responsibility for the attack but suspicion is likely to fall on ethnic Baloch separatists, who frequently target security forces and civilians in the region.
Interior Minister Mohsin Naqvi strongly condemned the attack and expressed deep sorrow over the children's deaths.
He called the perpetrators "beasts" who deserve no leniency, saying the enemy had committed an act of "sheer barbarism by targeting innocent children".
Officials, who initially reported that four children were killed but later revised the death toll to say two adults were also among the dead, said they fear the toll will rise further as several children were listed in critical condition.
The military also issued a statement, saying the bombing was "yet another cowardly and ghastly attack" allegedly planned by neighbouring India and carried out by "its proxies in Balochistan".
There was no immediate comment from New Delhi.
Most of the attacks in the province are claimed by the BLA, which Pakistan claims has India's backing.
India has denied such claims.
Prime Minister Shehbaz Sharif expressed his condolences and also blamed India, without providing any evidence to support the claim.
"The attack on a school bus by terrorists backed by India is clear proof of their hostility toward education in Balochistan," Sharif said, vowing that the government would bring the perpetrators to justice.
Pakistan regularly accuses India, its arch rival, for violence at home.
These accusations have intensified in the wake of heightened tensions between the two nuclear-armed nations amid a cross-border escalation since in April over the disputed Himalayan region of Kashmir, divided between the two but sought in its entirety by each.
Balochistan is a hub for Pakistan's ethnic Baloch minority, whose members say they face discrimination by the government.
In one of its deadliest recent attacks, BLA insurgents killed 33 people, mostly soldiers, during an assault on a train carrying hundreds of passengers in Balochistan in March.
And earlier this week, the BLA vowed more attacks on the "Pakistani army and its collaborators" and says its goal is to "lay the foundation for a peaceful, prosperous and independent Balochistan".
