The background to the controversy, he said, was the "wish of powers whose survival depends on creating crises".
The row began last week, when Pope Benedict XVI repeated criticism of the Prophet Muhammad by a medieval scholar.
The speech sparked worldwide protests by Muslims. The Pope has apologised and said the views quoted were not his own.
Ayatollah Khamenei said the remarks by Pope Benedict XVI last Tuesday were the "latest link" in "the chain of a conspiracy to set in train a crusade".
Other links, he added, included the cartoon satirising Muhammad and "the insulting remarks of some American and European politicians and newspapers about Islam".
Iran's supreme leader also said: "We do not expect anything from [US President George W] Bush, because he works for global, plundering companies and powers.
"But these remarks are very much a cause for regret and surprise from a senior Christian official."
Ayatollah Khamenei is the latest Muslim leader to condemn Pope Benedict's comments.
Influential Qatari Muslim scholar, Yusuf al-Qaradawi, called for a day of anger on Friday.
He also dismissed the Pope's expression of regret on Sunday, saying that the pontiff should retract his speech.
Sami Abu Zuhri, a spokesman for Hamas, which controls the Palestinian parliament, said: "We do not view the statement attributed to the Pope as an apology."
Activists held more protests against the Pope in various Muslim areas on Monday.
In Indian-administered Kashmir many schools and shops remained closed.
Demonstrators took to the streets in Iraq and Indonesia. In Syria, a rally was held at a mosque in Damascus.
The Pope on Sunday expressed regret for causing offence in last week's speech - delivered during a visit to his native Germany.
He said the medieval text he quoted, which said the Prophet Muhammad had brought the world only evil, did not in any way express his personal opinion.
"I am deeply sorry for the reactions in some countries to a few passages of my address at the University of Regensburg, which were considered offensive to the sensibility of Muslims," he told pilgrims.
"These in fact were a quotation from a medieval text, which do not in any way express my personal thought.
"I hope this serves to appease hearts and to clarify the true meaning of my address, which in its totality was and is an invitation to frank and sincere dialogue, with mutual respect."
Although some Muslims have rejected the apology, others have welcomed it.
The Council of Muslims in Germany said the Pope had taken an important step towards calming the unrest of the past few days.
The Muslim Council of Britain said the Pope's expression of regret was "exactly the reassurance many Muslims were looking for".
In Turkey, the most senior Muslim religious figure, Ali Bardakoglu, said the Pope's stated respect for Islam was a civilised position.
The government said the Pope was still expected to go ahead with a visit to Turkey in November
Popes Comments= http://news.bbc.co.u...ope/5348456.stm
I have to say that my personal opinion on this is that the comments were unnesasary and hypocritical, before talking about violence connected to other religions, he should perhaps explain the violence connected to the Christian faith