"The Americans have not respected their commitments," he said in the speech for Nowruz in the northeastern city of Mashhad.
The United States has lifted sanctions "on paper" under Tehran's nuclear deal with world powers that came into effect in January, "but they are using roundabout paths to prevent the Islamic republic from achieving its targets", Khamenei said.
"They have said they lifted the sanctions... but, in fact, they are working to prevent the lifting of sanctions from taking effect," he said.
The Nowruz holiday comes just two months after implementation of the deal began, triggering the lifting of a raft of international sanctions and raising the prospect of renewed foreign investment.
But Khamenei said the Western allies of Washington remained "afraid" of dealings with Iran.
"Today, in all the Western countries which are under their influence, banking transactions come up against problems," he said.
"When we investigated, we realised that they are afraid of the Americans."
In a pre-recorded television address broadcast earlier on Sunday, he said: "The economy must be our priority."
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The end of the 13-year standoff over Iran's nuclear programme has raised expectations of recovery after years of economic difficulty, including high inflation which dramatically reduced Iranians' purchasing power.
The economy exited a deep recession little more than a year ago.
But although international oil sales have resumed and exports risen since January, the price of crude means receipts have been low and growth remains weak.
"The solution is the economy of resistance," Khamenei said.
"With the economy of resistance, we can fight unemployment and recession, control inflation and confront the threats of enemies."
He said President Hassan Rouhani's government had put in place "extensive measures" to repair the economy.
"Steps have been taken and these preliminary actions must continue," the supreme leader said, in a possible nod to Rouhani's taming of inflation, which has fallen to 13 percent from more than 40 percent when the president took office in August 2013.
"I do not expect that these problems will be solved in a year, but I'm sure that if appropriate actions are taken, we will see the effects at the end of the year."
Unemployment in Iran stands at a little over 10 percent but youth unemployment is around 25 percent, making job creation vital.
In a separate message, broadcast immediately after Khamenei's, Rouhani echoed the supreme leader, and said economic growth of five percent was his aim for the next 12 months.
"I have hope, and am certain that with interaction with the world, we can move towards economic prosperity," he said.