The killings are thought to be the first US military fatalities in nearly three years in the country's border region with Afghanistan.
The US troops killed in the attack were apparently part of a little-publicised team in north-western Pakistan training local forces to combat al-Qaeda and the Taliban.
US defence officials say there are a total of about 200 US military personnel in Pakistan, including troops that guard the huge American embassy in Islamabad, Pakistan's capital.
More than 100 of those, though, are special operations forces training the Pakistani Frontier Corps, Reuters news agency has reported, citing an unnamed US defence source.
The Pakistani Taliban claimed responsibility for Wednesday's bombing, saying US forces were the target, and threatened more attacks.
But Richard Holbrooke, the US envoy to Pakistan and Afghanistan, has denied both that the training mission was secret and that the American forces were being targeted.
"They [the Taliban] are certain to say that, that's what they do - they're adept at propaganda and disinformation," Holbrooke said on Wednesday.
"The facts are the facts and when, at the appropriate moment, after appropriate notification of next of kin, the exact rank [of those killed] will be publicly disclosed as we always do. There's nothing secret about their presence there."
AP news agency, however, cited witnesses as saying the vehicle carrying US forces took the brunt of the explosion as their five-car convoy travelled along the road in Shahi Koto town, rather than the girl's school.
The three Americans killed were assigned to the US training mission there, but worked as "civil affairs" specialists, according to Reuters' defense officials, meaning that they coordinated with local mayors and tribal leaders.
The troops were apparently on their way to the opening of the newly-renovated girls' school, which had been blown up in January 2009 and was rebuilt with US funding.