The attack highlights the continuing dangers facing the US-led coalition as it winds down operations in Afghanistan with 51,000 combat troops due to pull out of the country by the year's end.
Sunday's incident occurred around 200 kilometres southeast of Quetta.
"Two gunmen riding a motorcycle intercepted a Nato oil tanker in Dera Murad Jamali city and fired bullets at it," local police official Ali Gohar Lehri told AFP.
"The tanker and a car close to it caught flames," he added.
"The driver and cleaner of the tanker and all passengers travelling in the car jumped out of their vehicles to save their lives."
The attackers escaped the crime scene. Another police official confirmed the shooting.
"The main highway between Sindh and Balochistan remained closed for around two hours because of the burning vehicles," Noor Muhammad Breach, a senior police official in the area, told AFP.
"Hundreds of vehicles were stuck on the highway," he added.
Pakistan has been a key transit route for the US-led mission in landlocked Afghanistan.
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