The 49-year-old shock rocker took to his Twitter account recently to tease his 1.38 million followers that the 'Pirates of the Caribbean' star may have been in talks to join him and his bandmates - Tyler Bates and Gil Sharone - as guitarist on a permanent basis.
It comes after bassist Twiggy Ramirez was axed from the touring group after being accused of rape.
Manson - whose real name is Brian Warner - tweeted: ''Johnny Depp is considering a position on guitar. Sound great? (sic)''
The high-profile duo have been friends for nearly two decades, and Hollywood legend Depp recently starred in two of his pal's music videos for 'KILL4ME' and 'Say10'.
The 54-year-old actor also frequently joins the 'Tainted Love' singer - who is godfather to Depp's 18-year-old daughter Lily-Rose Depp - on stage to play the stringed instrument.
The 'Lone Ranger' star has all the qualifications to make being a musician his main occupation as since 2015, he's been rhythm and lead guitar, backing vocals, slide guitar and keyboard player in the Hollywood Vampires - alongside Alice Cooper and Aerosmith's Joe Perry.
The 'Heaven Upside Down' hitmaker previously said he shares a lot in common with Depp.
He said: ''We were both white trash from hillbilly country, to use the vernacular, and sharpened our teeth in Florida.''
And they are more than comfortable in one another's company.
In the 'KILL4ME' promo, Depp simulates a threesome with two models.
The 'Dark Shadows' star can be seen getting extremely intimate with the girls played by Jocelyn Binder and Bailee Cowperthwaite in the X-rated video. Depp also burnt Manson's underwear, which ''embarrassed'' him in front of the women.
Of the bizarre video, Manson said: ''At the end, when you see the underwear burning, those are mine - and that's Johnny's lighter - he burnt my f***ing underwear!
''I was embarrassed to be nude in front of these two girls, Johnny too. We've been friends for so long but we don't sit around and look at each other's undercarriages.''
American Thighs was released on this day in 1994.