"We have no smoking gun that the Crown Prince was involved. Not the intelligence community or anyone else. We have no smoking gun," Mattis told reporters outside the Pentagon.
Mattis added that he has personally read all the intelligence on Khashoggi and all the translations of the recordings of his murder at the Saudi consulate in Turkey.
"We do not have the tapes. Least I am not aware that we do. But I have read the translation twice," he told reporters.
Secretary of State Mike Pompeo also told reporters earlier on Wednesday that he has read every piece of intelligence, but has not found "direct reporting" connecting bin Salman to Khashoggi's death.
Last week, US media reported that the CIA concluded bin Salman personally ordered the killing of Khashoggi.
Khashoggi went missing on October 2 after entering the Saudi consulate in Istanbul, and the Saudi Prosecutor General's Office has since concluded that he was killed inside the consulate by lethal injection before his body was dismembered and removed from the building.
