Obama acknowledged the "legitimate criticism" in the past that the legal framework governing drones has had shortcomings.
"It wasn't as precise as it should have been, and there's no doubt civilians were killed that shouldn't have been," he said at a news conference at the conclusion of a nuclear security summit in Washington. "We have to take responsibility where we're not acting appropriately, or just made mistakes."
Obama said that the new guidelines for strikes on ISIS -- which have expanded in recent weeks as the U.S. looks at a broader array of targets -- means they are not taking place where there are women, children or a normal civilian population.
"We've worked very hard to avoid and prevent" those strikes, he said. "Our operating procedures are as vigorous as they've ever been."
ISIS and the Iran nuclear deal were centerpieces of the summit, with Obama claiming the latter as a major foreign policy achievement.
The President on Friday said that Tehran is sticking to the "the letter" of its nuclear agreement and that as a result, the U.S. and other nations will work to help Iran integrate into the world economy.
The U.S. will soon move to ease the ban on Iran's use of U.S. dollars within the next few days, according to a report Friday by The Wall Street Journal. That move would make it much easier for Iranian companies to integrate back into the international financial and trade system.
"So long as Iran is carrying out its end of the bargain, we think it's important for the world community to carry out our end of the bargain," Obama said at the end of the summit, which drew more than 50 world leaders to Washington.
"We want to make sure that over time they're in a position to realize those benefits," as long as they adhere to their commitments, Obama said.
The move, however, has been met with criticism by opponents of the nuclear deal, who fear it will only embolden Iran and make it more likely to break its commitments.
The summit, the last of four Obama has held during his presidency, focused on the threat of nuclear terrorism. Obama held up the nuclear agreement with Iran as an example of progress that can be made when countries unite behind strong diplomacy.
Obama hosted a side meeting during the summit with members of the so-called P5+1, the group of countries -- France, the U.K., Germany, Russia, China and the U.S. -- that negotiated the deal with Iran. They were told by the U.N.'s International Atomic Energy Agency that Iran is implementing steps required under the deal, Obama said.
"As a consequence, sanctions related to their nuclear program have been brought down," Obama said, but he noted Iran's unhappiness that easing sanctions haven't resulted in a rush of international investment.
"Part of the challenge they face is that companies haven't been doing business there for a long time and they need to get comfortable with the prospect," Obama said.
Treasury Secretary Jack Lew will be working to offer "clarity" to companies about whether they can or can't get involved in various business agreements in Iran, Obama said.
But even if Iran is complying with the letter of the law, Obama said, businesses will still be leery if Tehran doesn't also reflect the spirit of the agreement.
"What's also important is Iran's own behavior," Obama said.
Businesses want to go where they feel safe, where they don't see massive controversy, and "where they can be confident transactions will operate normally," the President said.
Iran has to "signal it is not going to be engaging in provocative actions that might scare business off," Obama said. "When they launch ballistic missiles with slogans calling for the destruction of Israel, that makes businesses nervous," Obama said. "When Iran continues o ship missiles to Hezbollah, that makes business nervous."
Obama said he suspected there were multiple power centers inside Iran's political elite and pointed the finger at the country's hardliners for those provocations, implying that they may be trying to undermine the deal.
He compared them to "hardliners in the United States," who even after certification that the Iran deal is working "are still opposed to the deal in principle."