The former Liverpool and United striker has labelled the decision to drop Rooney to the bench a "real kick in the teeth".
And Owen fears the move could signal a summer exit for the England superstar.
He pointed to other high-profile players axed for major games by Sir Alex Ferguson – a sign they were surplus to requirements.
David Beckham and Ruud van Nistelrooy were ruthlessly shipped out, while Roy Keane and Jaap Stam discovered big reputations count for nothing when Ferguson decides to act.
Rooney's exclusion split fans after the heartbreak of the 2-1 defeat had United crash out of the Champions League at the quarter-final stage on a 3-2 aggregate.
Owen said: "For Rooney not to start is a real kick in the teeth and it's got to be a big worry for him.
"It's the biggest game of the season and the manager has shuffled his pack and not included him. Wayne will take it one of two ways.
"He will either get his head down, try to improve and force his way back into the team, or he'll think, 'The manager has not picked me for the biggest game, he obviously doesn't fancy me', and it might not be the end of the story."
Meanwhile, Uefa last night opened disciplinary proceedings against United over Nani's red card and the non-fulfilment of post-match media obligations after the match.
Ferguson reacted angrily after Nani was controversially sent off for a high challenge on Madrid's Alvaro Arbeloa in the 56th minute while United were leading 1-0.
But with the man advantage, Madrid stormed back to win 2-1 on the night with former Old Trafford hero Cristiano Ronaldo bagging the vital second goal.
Ferguson did not appear for interviews after the match, with his assistant Mike Phelan attending the post-match press conference
He said the manager was too "distraught" to speak, while the players did not stop to talk in the mixed zone.