"I will destroy anyone who tries to hinder our decisions," Bashar al-Assad told al-Hariri during a meeting in Damascus, Khaddam told Dubai-based television channel al-Arabiya in an interview from Paris on Friday.
Khaddam said the meeting took place a few months before the bomb attack that killed al-Hariri in Beirut in February. A UN investigation has implicated Syrian intelligence services in the attack.
The Syrian intelligence services could not have carried out such an operation without al-Assad being informed, Khaddam said, when asked if the head of state could have been unaware.
"We must await the results of the investigation, but no Syrian security service could take such a decision unilaterally," he said.
Khaddam said he had advised al-Hariri "to leave Lebanon because his situation regarding Syria had become complicated" in the wake of the threat. "But, of course, at no time did it occur to me that Syria could assassinate Hariri."
In late March, Syria denied a report from a UN fact-finding mission that al-Assad had threatened al-Hariri and Walid Jumblatt, Lebanon's Druze leader, if they opposed the policies of Damascus.
Khaddam also pointed a finger of blame at Rustom Ghazaleh, Syria's military intelligence chief and vice-consul in Lebanon before its troop withdrawal in April after a 29-year deployment.
"Rustom Ghazaleh behaved as if he had absolute power" in Lebanon, Khaddam said. He said that he had failed to convince al-Assad to have him replaced.
Khaddam, 73, widely regarded as the architect of Syrian policy towards Lebanon before its troop withdrawal, also gave the reasons for his resignation in June.
He said he was "convinced that the process of development and reforms, be they political, economic or administrative, will not succeed" and preferred to choose "the motherland" over "the regime".
"I have many things to say, serious things, when the time is right," he said. He also said that his relationship with al-Assad remained "amicable".
Khaddam, who served Bashar's father, Hafez, before his death in 2000, was also close to Ghazi Kanaan, Syria's intelligence chief in Lebanon who committed suicide in October.
Lebanese media speculated at the time that Kanaan, who held the post before being replaced by Ghazaleh, had been killed because he was about to reveal who arranged al-Hariri's killing.
Khaddam now lives in Paris, where he said he was writing a book, and, like Kanaan, was also close to the pro-Western al-Hariri.
Kanaan and Khaddam were reportedly stripped of responsibility for the Lebanon file by al-Assad, in keeping with an agreement with Emile Lahoud, Lebanon's pro-Syrian president, who accused both men of being in al-Hariri's pay.