Khamenei said on Tuesday: "If the Iranian officials can make the US understand some issues about Iraq, there is no problem with the negotiations."
It was the first confirmation that Khamenei, who holds final say on all state matters in Iran, is in favour of the talks.
"But if the talks mean opening a venue for bullying and imposition by the deceitful party [the Americans], then it will be forbidden," he said in a nationally televised speech in Mashhad in northeastern Iran.
America and Iran have said the talks will focus solely on stabilising Iraq and not deal with Iran's nuclear programme. No time or place has been set for talks, but Zalmay Khalilzad, the US ambassador to Iraq, who is to head the US side, has proposed holding them in Baghdad.
"But if the talks mean opening a venue for bullying and imposition by the deceitful party [the Americans], then it will be forbidden"
Ayatollah Ali Khamenei,
Iran's supreme leader
Last week, a senior Iranian official - Ali Larijani, the secretary of the Supreme National Security Council - announced that Tehran was willing to enter talks with the United States.
Khamenei voiced his approval on Tuesday after some hard-liners in Iran's clerical government came out against any contacts with the United States.
Iran has influence on Shia political parties, which dominate Iraq's parliament, and Condoleezza Rice, the US secretary of state, has said US-Iranian talks on Iraq could be useful.
The Bush administration has accused Iran's Revolutionary Guard of smuggling bomb-making parts across the border into Iraq, though General Peter Pace, chairman of the Joint Chiefs of Staff, said last week he had no evidence that Iran's government was behind such an activity.
Bomb attacks have mainly been carried out by Sunni insurgents attacking the Shia-led Iraqi government.
Also in Tuesday's speech, Khamenei has dismissed the threat of UN Security Council action over Iran's nuclear programme, saying Tehran will reject any measures it considers against its interests.
Khamenei made the comments as the five permanent members of the Security Council continued to debate what action to take, with Iran's allies Russia and China against British attempts to draw up a statement demanding Tehran should give up uranium enrichment.
"If it is against the interests of our country, we do not accept it. They threatened us with the Security Council as if the council is the end of the world," Khamenei said.