James Bays, Al Jazeera's correspondent in Islamabad, said official sources had confirmed to him that heavy artillery was being used in Makeen.
Pakistan's Geo TV reported that large numbers of people were migrating from South Waziristan to North Waziristan.
"Operations that appear to be under way now would be the largest operations that have been undertaken in Waziristan," a US defence official said on Friday.
"We think that the initial phases of that operation have already begun."
Pakistan says it has almost completed an offensive to drive Taliban fighters out of the Swat valley, an adjoining area in North West Frontier Province (NWFP).
The US defence official said on Friday that the Pentagon expected Pakistan to conduct "fairly significant combat operations in South Waziristan".
Another US official said Taliban and al-Qaeda leaders were "under very significant pressure", while a third US official said the US would be providing increased intelligence and surveillance support to Pakistan.
Pakistan's recent operations have been under way for six weeks, taking the military first into Buner and Upper Dir districts, then into the Swat valley.
The first US official warned that "isolated pockets of resistance still remain" in parts of Swat as the Pakistani army worked to finish the two-month campaign, and that Islamabad needed to brace for more attacks.
"[Mehsud] has turned suicide bombing into a production output not unlike Toyota outputs cars," the official, who described the Mehsud as leading an extensive network of religious schools that sold or bartered child suicide bombers in NWFP, said.
The key element of the US Afghanistan-Pakistan strategy, the defence official said, is to have troops put pressure on al-Qaeda and Taliban fighters believed to be operating out of safe havens in Waziristan.
Asif Ali Zardari, the Pakistani president, said on Saturday he would fight the Pakistani Taliban "to the end".
"This war has the support of parliament, the support of the political parties as well as the people of Pakistan," he said in a televised address to the nation broadcast after 1am (1900 GMT) on Friday.
"We are fighting a war for our sovereignty. We will continue this war until the end, and we will win it at any cost," Zardari said.
"These people want to capture the institutions of Pakistan by spreading terrorism and by intimidating the people.
"They have killed thousands of innocent people."
Zardari's comments came after two suicide bomb attacks in Lahore and Nowshera, in NWFP, killed at least eight people, including a pro-government religious leader, on Friday.
Maulana Sarfraz Naeemi, known to oppose the Taliban, had condemned the use of suicide bombings.
Thousands gathered under tight security for Naeemi's funeral on Saturday in Lahore, many demanding death for Mehsud.
The killing sparked a general strike that virtually shut down Karachi, Pakistan's commerical centre.
About 200 activists of Jamat Ahle Sunnat, a moderate Muslim sect, staged a mock funeral procession for the Taliban, burning one in effigy as they chanted "Down with the Taliban; Taliban, the enemy of Islam; death for the killers of Sarfraz Naeemi".