Armstrong founded the cancer charity in 1997 after recovering from the disease.
His resignation comes a week after the US Anti-Doping Agency said it has overwhelming evidence of his involvement in a doping program. Armstrong has consistently denied the claims.
According to a statement on the group’s website, he said his decision was made to “spare the foundation any negative effects as a result of controversy surrounding my cycling career.”
The move also comes the same day that Nike, a key Armstrong sponsor, announced it was ending its contract with him.