Coming from Mullen, who's known as the "good cop" on the U.S. side of the rocky relationship, the comments also seemed to acknowledge the failure of an Obama administration policy to persuade Pakistan's military to cut ties with Afghan insurgents and close their bases on its side of the border in return for billions of dollars in U.S. aid, training, and weaponry.
The development potentially holds serious implications for the U.S.-led military campaign to crush the Taliban-led insurgency in Afghanistan. The administration's strategy there has in part counted on improved cooperation from the Pakistani military in routing militants from their tribal region.
Pakistan's premier spy agency, the Inter-Services Intelligence Directorate, or ISI, has a "relationship" with the Haqqani network, a group close to the Afghan Taliban and al-Qaeda, that ends up costing the lives of American soldiers in Afghanistan, Mullen said.
"The ISI has a long-standing relationship with the Haqqani network. That doesn't mean everybody in the ISI. But it's there," Mullen said on Geo News, Pakistan's leading news channel. "I believe over time that's got to change."
He made similar remarks in separate interviews with two Pakistani newspapers.
Pakistan denies supporting Haqqani or other militant groups but acknowledges keeping open channels of communication with them, as spy agencies often do. The Pakistani military says it's too stretched elsewhere to mount an operation against the Haqqani network, which is based in North Waziristan.
Moeen Yusuf, an expert with the U.S. Institute of Peace in Washington, said the two sides were about as close to a "rupture" in relations as they had ever been. A rupture would be costly for both sides: The U.S. relies on the ISI for intelligence on al-Qaeda, and Pakistan depends on the United States for economic and military assistance.
Mullen's remarks show "just how bad the relationship is all around," Yusuf said.
The testy relationship has been frayed by a series of events during the last 11 months, culminating in the arrest in January of Raymond Davis, an American contractor working for the CIA, after he shot dead two Pakistani men in Lahore he said had been trying to rob him at gunpoint.
Davis' arrest exposed secret CIA operations against Islamic extremist groups considered close to the ISI, which has historically nurtured such groups to fight as its proxies in India and Afghanistan.