The singer, who scored a massive international hit with her cover of Prince's Nothing Compares 2 U, blamed Arsenio for providing the music icon with drugs that may have killed him in a bizarre post on her Facebook page.
Sinead wrote: "Two words for the DEA investigating where (sic) prince got his drugs over the decades... Arsenio Hall (AKA Prince's and Eddie Murphy's b**ch)."
TMZ reports the Irish star has actually reported Arsenio to officials at the Carver County Sheriff's department, who are investigating Prince's death.
The unprovoked attack and claims prompted a quick response from Hall's aides, who shot down Sinead's comments on Monday (02May16).
A rep for Arsenio insists her allegation is "absolutely false, ridiculous and absurd."
Sinead has made previous claims against Prince himself, accusing the late music legend of punching her and holding her against her will.
Speaking about her relationship with Prince in an interview in Norway in November 2014, O'Connor said, "I did meet him a couple of times. We didn't get on at all. In fact, we had a punch-up.
"He summoned me to his house after Nothing Compares 2 U. I made it without him. I'd never met him... He said he didn't like me saying bad words in interviews. So I told him to f**k off! He got quite violent. I had to escape out of his house at five in the morning. He packed a bigger punch than mine."
Prince died at his Paisley Park compound in Minnesota last month (21Apr16).
Unconfirmed reports suggest he was struggling with a dependency on painkillers for a hip injury in the weeks leading up to his death.
An autopsy carried out on the day after his passing proved inconclusive and results from tests to determine a cause of death will not be available for weeks.