In an interview with the BBC, Mr Obama said it was "distressing" not to have made progress on the issue "even in the face of repeated mass killings".
He vowed to keep trying, but the BBC's North America editor Jon Sopel said the president did not sound very confident.
However, Mr Obama said race relations had improved during his presidency.
Hours after the interview, a gunman opened fire at a cinema in the US state of Louisiana, killing two people and injuring several others before shooting himself.
Mr Obama lands in Kenya later on Friday for his first visit since becoming president.
But with just 18 months left in power, he said gun control was the area where he has been "most frustrated and most stymied" since coming to power in 2009.
"If you look at the number of Americans killed since 9/11 by terrorism, it's less than 100. If you look at the numbers that have been killed by gun violence, it's in the tens of thousands," Mr Obama said.
"For us not to be able to resolve that issue has been something that is distressing," he added.
Mr Obama has pushed for stricter gun control throughout his presidency but has been unable to secure any significant changes to the laws.
After nine African-American churchgoers were killed in South Carolina in June, he admitted "politics in this town" meant there were few options available.