"I am embarrassed for them," Obama said in an interview with Vice media, which is expected to be released Monday.
"For them to address a letter to the Ayatollah who, they claim, is our mortal enemy and their basic argument to them is: don't deal with our president because you can't trust him to follow through on an agreement. It's close to unprecedented."
Forty-seven Senate Republicans -- including several potential 2016 presidential candidates -- signed the open letter to Iran's supreme leader published earlier this month.
"The next president could revoke such an executive agreement with the stroke of a pen and future Congresses could modify the terms of the agreement at any time," they added.
With a March deadline looming, negotiators are furiously working to agree on a deal that would curb Iran's nuclear program in return for reducing Western sanctions.
A new round of talks between US Secretary of State John Kerry and Iranian Foreign Minister Mohammad Javad Zarif is due to take place in Lausanne, Switzerland on March 15.