Demonstrators left the capital Islamabad Saturday morning destined for Kotkai in South Waziristan, Dawn News reported.
Kotkai, in the northwest tribal region, is the hometown of Qari Hussain, who is said to have been killed in a drone strike in 2010. He was the main trainer of Taliban suicide bombers in Pakistan.
The northwest tribal areas are routinely targeted by missiles fired by U.S. drones.
The marchers were expected to be joined along the way by activists from Rawalpindi and other cities.
Some 30 anti-drone activists from the United States were reportedly taking part in the demonstration.
The march was organized by Imran Khan, chief of Tehrik-i-Insaf (PTI), considered to be a centrist progressive political party said to be the fastest growing in Pakistan.
Hundreds of supporters carrying green and red PTI banners gathered along the route to cheer on Khan and his convoy of about 100 vehicles.
The march is proceeding without government security. Khan, who has political ambitions, charged the government wanted to stop the march.
The Khyber Pakhtunkhwa government will provide 400 additional officers along part of the route.
The Taliban denied reports it would aid with security, calling Khan "a liberal and secular person."
A report commissioned by Reprieve, Stanford Law School and the New York University School of Law last month estimated that 474 to 881 civilians were among 2,562 to 3,325 people killed by drones in Pakistan between June 2004 and September 2012.
Beautician charged with giving client fatal silicone butt injection
Attkisson leaves CBS News, reportedly over network's 'liberal bias'