"These strikes are a violation of Pakistan's sovereignty and territorial integrity. There is an across the board consensus in Pakistan that these drone strikes must end," Pakistan foreign office said in a statement.
The drone attack, carried out in the tribal region's Danday Darpa Khel area in the evening, killed a total of six people.
Mehsud's close aide Tariq Mehsud was also among the six killed, security sources said.
Pakistani Interior Minister Chaudhry Nisar Ali Khan refused to confirm the death of Tehreek-e-Taliban Pakistan (TTP) chief.
Also, the TTP neither confirmed nor denied its chief's death by the drone strike.
Hakimullah Mehsud had replaced Baitullah Mehsud as TTP chief after the latter was killed in a US drone strike in 2009.
Meanwhile, following the attack, Interior Minister Khan termed the attack an attempt to sabotage the government's plan to hold talks with the Taliban.
The Pakistan Taliban have also been demanding from the government to get the US drone strikes stopped before talks.
Hafiz Muhammad Saeed, founder of Lashkar-e-Taiba terror group that staged the 2008 Mumbai attacks and the Jamat -ud- Dawa chief, Friday urged the Pakistan government to shoot down US drone to convey a message to the US that the strikes were tantamount to attack on Pakistan's sovereignty.
"It is incumbent upon the government to shoot down drone" he said, during an anti-US drone attacks protest, and welcomed cricketer-turned politician Imran Khan's statement in which he warned of blocking the NATO supplies if drone strikes were not stopped.
He also claimed that the US and India wanted to sabotage Pakistan's peace talks with the Taliban.
The Friday's strike was the second drone attack since Pakistan Prime Minister Nawaz Sharif visited the US, where he demanded President Barack Obama to stop the attacks.
Pakistan has long been opposing CIA-operated drone attacks in the tribal region dubbing them as violation of its territorial integrity.