The guiding assumption behind the administration’s policy is that Iran is economically weak, has little interest in a military confrontation with the U.S.—and that Washington can force changes in decadeslong Iranian behavior that will reconfigure the Middle East, officials and experts say.

But senior Iranian officials insist Tehran will neither retrench nor negotiate. Former U.S. officials with long experience say Tehran has cards to play, including trying to ride out the sanctions in the hope that Mr. Trump is a one-term president and taking advantage of the continued turmoil in the region to stir up fresh challenges for the U.S. and its allies.

“Iran is gaining ground in the region, and I don’t see these sanctions as reversing that,” said Jeffrey Feltman, who was the top State Department official on Middle East issues from 2009 to 2012 and later served as a United Nations undersecretary general for political affairs.