Clinton made the comments to a group of newspaper editors in the Pakistani city of Lahore on Thursday, a day before the final leg of her trip to the country.
Al Jazeera's Nick Spicer in Washington DC, said: "It provoked surprise here in Washington, but relief as well.
"American decision-makers have long suspected that al-Qaeda leaders are being given refuge in Pakistan, but they haven't said that publicly."
Clinton said in an interview shown on NBC's Today Show: "I wanted to get that out on the table, because the Pakistanis have talked about a trust deficit and it's a two-way street.
"We have questions, they have questions," she said.
In an interview aired on ABC's "Good Morning America," Clinton said the two countries needed to be more open with each other.
Al Jazeera's Imran Khan reports from the frontline in South Waziristan
"I want to have the kind of relationship where we really are talking honestly about everything between us - because there's just too much at stake.
"It will not be sufficient to achieve the level of security that Pakistanis deserve if we don't go after those who are still threatening not only Pakistan but Afghanistan and the rest of the world."
In an interview with CNN, Clinton noted that she had been asking a question of Pakistan but did prejudge the answer. She also said the United States applauded Pakistan's resolve for going after Taliban extremists.
"But let's not forget, they [the Taliban fighters] are now part of a terrorist syndicate that, in sort of classic syndicate terms, would be headed by al Qaeda," she said.
"Maybe that's the case. Maybe they're not gettable. I don't know."
Al-Qaeda leaders are widely believed to be hiding in a remote mountainous region along Pakistan's border with Afghanistan.
There was no immediate reaction from Pakistan's government following her comments.
Clinton also used her visit to tackle anti-American sentiment that is believed to be undermining US allies in the Pakistani government.
"I am more than willing to hear every complaint about the United States," she said.
Anne Patterson, the US ambassador to Pakistan, said Clinton's remarks approximate what the US administration has told Pakistani officials in private.
"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."
Clinton's visit came as Pakistan's military continued to fight Taliban members in South Waziristan as part of an offensive that Washington has welcomed.