Addressing a crowd of tens of thousands in the eastern city of Lahore he said his Tehreek-e-Insaf party would like to have friendly -- but not slavish -- relations with the US.
"My message to America is that we will have friendship with you but we will not accept any slavery," he told the crowd.
"We will help you in a respectable withdrawal of your troops from Afghanistan, but we will not launch a military operation in Pakistan for you."
Witnesses said the rally, one of the largest in the city, was attended by some 150,000 people while organisers put the number at over half a million.
People came in packed buses, trucks, cars and tractors from Lahore and other cities including those in the northwestern Khyber Pakhtunkhwa province bordering Afghanistan. Roads were blocked for hours due to heavy crowds.
"Who will save Pakistan? Imran Khan, Imran Khan," the crowd chanted as Khan arrived at the sprawling Minar-e-Pakistan ground ringed by security forces.
Vowing to end terrorism in the country, Khan said he held a meeting with tribal elders three days ago.
"They all said militancy will end if Pakistan army leaves the tribal areas and US troops quit Afghanistan," he said.
There is widespread anti-Americanism in Pakistan as well as opposition to the drone strikes, although the attacks have never mobilised a widespread public movement.
Vowing to end corruption, poverty and illiteracy, and to depoliticise the police, Khan said his party would provide justice at village level.
He warned that he would launch a civil disobedience campaign if the country's rulers did not declare their assets over the next few months.
"We will launch a civil disobedience movement and our youth will shut down cities across the country if you don't declare your assets," he said.
The rally, seen as a show of strength, comes two days after the main opposition leader Nawaz Sharif's brother Shahbaz, attracted some 30,000 people at an anti-Zardari protest also in the key political battleground of Lahore.
Pakistan Muslim League-N (PML-N) demanded early elections in its political heartland -- it controls the Punjab provincial government despite being in opposition at national level.
"People including youth, and intelligentsia responded to his call. This shows people want a change," he said.
"People see a new option in him. How much impact it will have on the next elections is yet to be seen."
Copyright AFP (Agence France-Presse), 2011