He made these comments at the National Defense University on Thursday. He also acknowledged the targeted strikes are no "cure-all" and said he is haunted by the civilians unintentionally killed.
Since taking office, Mr. Obama's counterterrorism strategy has relied more on the use of strikes by unmanned spy drones, particularly in Pakistan and Yemen. The secretive program has faced criticism from congressional lawmakers who have questioned its scope and legality.
The president defended the drones' targeted killings as effective and legal. He acknowledged the civilian deaths that sometimes result - a consequence that has angered many of the countries where the U.S. seeks to combat extremism - and said he grapples with that trade-off.
"For me, and those in my chain of command, these deaths will haunt us as long as we live," he said. Before any strike, he said, "there must be near-certainty that no civilians will be killed or injured - the highest standard we can set."
Before his speech, Mr. Obama signed new "presidential policy guidelines" meant to clarify to Congress and to the public the standards the U.S. applies before carrying out drone attacks.
Officials said the guidelines include not using strikes when the targeted people can be captured, relying on drones only when the target poses an "imminent" threat and establishing a preference for giving the military control of the drone program.
In Pakistan alone, up to 3,336 people have been killed by the unmanned aircraft since 2003, according to the New America Foundation which maintains a database of the strikes.
The president's advisers said the new guidelines will limit the number of drone strikes in terror zones and pointed to a future decline of attacks against extremists in Afghanistan as the war there winds down next year. But strikes elsewhere will continue. The guidelines will also apply to strikes against both foreigners and U.S. citizens abroad.
A day before Mr. Obama's speech, his administration revealed for the first time that a fourth American citizen had been killed in secretive drone strikes abroad. The killings of three other Americans in counterterror operations since 2009 were widely known before a letter from Attorney General Eric Holder to Senate Judiciary Committee Chairman Patrick Leahy acknowledged the four deaths.
Though the president sought to give more transparency to the drone program, the strikes will largely remain highly secret for the public.
Also Thursday, Obama reaffirmed his stalled 2008 campaign promise to close the military prison at Guantanamo Bay, where some terror suspects are held. Lifting the ban on transfers of some Guantanamo prisoners to Yemen is a key step in jumpstarting that process, given that 30 of the 56 prisoners eligible for transfer are Yemeni.
The Associated Press contributed to this report.