The Discovery is on a pivotal mission to the International Space Station, and took off despite lingering safety concerns, three years after the Columbia tragedy.
Seven astronauts, including two women, are now en route to the ISS on a mission aimed at improving shuttle safety.
Shuttle program manager Wayne Hale said the falling debris could have been foam insulation.
"About two minutes and 47 seconds give or take (after the launch), we saw three perhaps four pieces come off," said Mr Hale, adding that it was unclear whether it was foam or "something else."
"We also saw another piece or two come off at about four minutes 50 seconds," he told reporters at the Kennedy Space Centre in the US state of Florida.
Raw data
He cautioned, however, that it was "very raw, preliminary data" and would have another report later Tuesday.
But Mr Hale said the debris came off the fuel tank later than officials feared and it could have damaged the shuttle's heat shield.
"Both of those (losses of debris) are interesting because they are after the time we're concerned about aerodynamic transport causing damage to the shuttle tiles," he said. He did not say what size the debris was.
NASA officials had expected some foam to come off during lift-off, but that it would not be of a size that would endanger the shuttle.
A small piece of foam fell off Discovery's fuel tank a day before the launch, but officials decided the shuttle could fly safely without repairing the gap.
The Columbia shuttle disintegrated upon re-entry into the Earth's atmosphere in February 2003, when loose foam that came off during lift-off pierced its heat shield.
The Discovery launch had been twice delayed due to weather concerns, before launching on US Independence Day.
A new crack in foam insulation earlier this week prompted concerns over safety. However, NASA Administrator Michael Griffin chose to go ahead with the launch.
Safety procedures
During the 12-day flight, the astronauts will test new procedures to boost safety as well as deliver critical equipment and supplies to the ISS.
They will drop off European Space Agency astronaut Thomas Reiter of Germany, who will join the ISS's two other crew members for a long-term stay, and undertake two space walks.
NASA hopes to extend the mission by a day to conduct a third space walk to test new repair techniques.
The space agency has installed cameras on the shuttle and its fuel tank to detect any loss of foam during lift-off.
The shuttle's heat shield will then be photographed as it approaches the ISS.
NASA wants to conduct four missions a year to complete the space station by 2010, when the space shuttle fleet is scheduled to retire.