The longtime foes have held five rounds of talks since April to thrash out a new accord to replace the deal with major powers that US President Donald Trump abandoned during his first term in 2018.
On Saturday, Iran said it had received "elements" of the US proposal through Omani mediators, the details of which have not been publicly disclosed.
"The proposal presented by the Americans is 100 percent against" notions of independence and self-reliance, Khamenei said in a televised speech, invoking ideals of the 1979 Islamic revolution.
"Independence means not waiting for the green light from America and the likes of America."
Iran's enrichment of uranium has emerged as a major point of contention.
Trump said on Monday his administration would not allow "any" enrichment, despite Tehran's insistence it is its right under the nuclear Non-Proliferation Treaty.
Khamenei said enrichment is "key" to Iran's nuclear programme and that the United States "cannot have a say" on the issue.
"If we have 100 nuclear power plants but don't have enrichment, they will be of no use to us," because "nuclear power plants need fuel" to operate, he said.
"If we cannot produce this fuel domestically, we have to reach out to the United States, which may have dozens of conditions."
The New York Times reported Tuesday that the US proposal includes "an arrangement that would allow Iran to continue enriching uranium at low levels" as the US and other countries "work out a more detailed plan intended to block Iran's path to a nuclear weapon".
It said the proposal would see the United States facilitating "the building of nuclear power plants for Iran and negotiate the construction of enrichment facilities managed by a consortium of regional countries".
Iran has previously said it is open to temporary limits on its enrichment of uranium, and is willing to consider the establishment of a regional nuclear fuel consortium.
But it has stressed that such a consortium is "in no way intended to replace Iran's own uranium enrichment programme".
Iran's chief negotiator, Foreign Minister Abbas Araghchi, said in a Wednesday post on X: No enrichment, no deal. No nuclear weapons, we have a deal."
- 'Less than satisfactory' -
On Monday, Araghchi held talks in Cairo with Rafael Grossi, head of the UN nuclear watchdog, the International Atomic Energy Agency.
In its latest quarterly report last week, the IAEA said Iran had further stepped up its production of highly enriched uranium.
In a separate report, it also criticised "less than satisfactory" cooperation from Tehran, particularly in explaining past cases of nuclear material found at undeclared sites.
Iran currently enriches uranium to 60 percent, far above the 3.67-percent limit set in the 2015 deal but still short of the 90 percent threshold needed for a nuclear warhead.
The reports came ahead of a planned IAEA Board of Governors meeting in Vienna later this month which will review Iran's nuclear activities.
Washington and other Western governments have continued to accuse Iran of seeking a nuclear weapons capability. Iran insists its programme is for peaceful purposes only.
The 2015 deal provided Iran with relief from international sanctions in return for UN-monitored restrictions on its nuclear activities.
Trump reimposed US sanctions when he quit the agreement in 2018 and has since tightened them with secondary sanctions against third parties who violate them.
Britain, France and Germany, the three European countries who were party to the 2015 deal, are currently weighing whether to trigger the sanctions "snapback" mechanism in the accord.
The mechanism would reinstate UN sanctions in response to Iranian non-compliance -- an option that expires in October.
Iran has criticised the IAEA report as unbalanced, saying it relied on "forged documents" provided by its arch foe Israel.
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