Clinton said that al-Qaeda had enjoyed a "safe haven" in Pakistan since 2002.
"I find it hard to believe that nobody in your government knows where they are and couldn't get them if they really wanted to"
One of Clinton's principle objectives during her trip is to tackle the anti-American sentiment which is said to be undermining its allies in the Pakistani government.
"I am more than willing to hear every complaint about the United States," Clinton said.
"But this is a two-way street. If we are going to have a mature partnership where we work together" then "there are issues that not just the United States but others have with your government and with your military security establishment."
Clinton was keen to hail the US relationship with Pakistan.
"What we have together is far greater than what divided us," she told students at Lahore University, referring to her relations with Barack Obama, the US president.
"And that is what I feel about the United States and Pakistan."
Washington has welcomed the Pakistani military offensives against Taliban groups in North West Frontier Province and, more recently, in South Waziristan.
But there seems to have been little progress over the years in capturing or killing senior figures from the al-Qaeda movement.
Anne Patterson, the US ambassador to Pakistan, said Clinton's remarks approximate what the US administration has told Pakistani officials in private.
Al Jazeera's Imran Khan reports from the frontline in South Waziristan
"We often say, 'Yes, there needs to be more focus on finding these leaders,'" she said.
"The other thing is, they lost control of much of this territory in recent years and that's why they're in South Waziristan right now."
Patterson's predecessor, Wendy Chamberlin, told Al Jazeera that Clinton's comment reflected a widespread feeling among US officials over Pakistan's commitment to hunting down al-Qaeda
"I think there is a frustration that a lot of us have felt," she told Al Jazeera in Washington DC.
"Because we haven't been more effective since 2002, the extremism threat seems to have grown."
Clinton also faced questions from students, with many voicing doubts that the US could be a reliable and trusted partner for Pakistan.
One woman asked whether the US can be expected to commit long term in Afghanistan after abandoning the country after Russian occupiers retreated in 1989.
"What guarantee can Americans give Pakistan that we can now trust you - not you but, like, the Americans this time - of your sincerity and that you guys are not going to betray us like the Americans did in the past when they wanted to destabilise the Russians?" the woman asked.
Clinton responded that the question was a "fair criticism" and that the US did not follow through in the way it should have.
"It's difficult to go forward if we're always looking in the rear-view mirror," Clinton said.