Keane expressed his view after Rooney was an unused substitute in the 2-1 win over Anderlecht in the Europa League quarter-finals at Old Trafford.
The 31-year-old Rooney, United's all-time leading scorer with 250 strikes, has been reduced to a bit-part player role under Jose Mourinho this season.
Keane told ITV after the game on Thursday: "In terms of the bigger picture I'd have thought that's the end of Wayne at Manchester United.
"He will obviously contribute until the end of the season because of injuries.
"But he must be fuming not to be brought on. I think that's the final nail in the coffin for him, definitely.
"Leading scorer at the club, I'd expect him to be fuming, if he’s not fuming then he’s obviously lost the eye of the tiger. He must be like a mad man tonight, he must be."