In his first meeting with the newly appointed President Masoud Pezeshkian's government, Khamenei said that "it cannot harm" to engage in a dialogue.
But in the same breath, he warned against Washington.
Do not trust the enemy, he said.
It does not mean that we cannot interact with the same enemy in certain situations. It does not harm to do so, but have no hopes of results.
The US State Department responded to Khamenei's words by saying "we judge Iran by their actions, not what they say".
Iran broke off talks about the country's nuclear energy program in May. The reason given was the death of the Iranian President Ebrahim Raisi in a helicopter crash.
According to a report from the UN's atomic energy agency IAEA, the country had over 6,200 kilograms of enriched uranium in May – more than 30 times the maximum limit set in the 2015 nuclear agreement.
Of that amount, 142 kilograms were enriched to 60 percent purity, which, according to the IAEA, is only a short technical step from 90-percent weapons-grade uranium.
IAEA chief Rafael Grossi has also warned that Tehran has enough enriched uranium to produce "several" atomic bombs if the country chooses to do so.
Iran has in recent years deactivated IAEA monitoring equipment at nuclear power plants and hindered inspectors, according to the UN agency.