Manager Louis van Gaal confirmed on Friday that Rooney, Martial and Marouane Fellaini will all be absent at Vicarage Road for the lunch-time kick-off in which a win for United would put them provisionally top of the table.
Martial is missing with the foot injury he sustained in France's 2-0 defeat to England at Wembley on Tuesday night, although it is not thought to be a serious problem.
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Captain and leading scorer Rooney reported back from that game with an illness and Fellaini has failed to recover from a calf injury which kept him out of Belgium's friendly win over Italy last Friday.
Van Gaal said: "That's a big blow because Rooney is ill, so we have a big problem, I think.
Louis van Gaal tells #MUTV Carrick, Martial, Fellaini and Valencia are all injured, while Rooney is ill. All will miss Watford.
— Manchester United (@ManUtd) November 20, 2015
"Rooney was ill after the international break. I have only seen him the day after he played and then he was at home. Yesterday he was at home so I don't think he can play either."
Teenager James Wilson is United's only fit recognised striker but the 19-year-old is short of match fitness and not considered ready to play 90 minutes.
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Memphis Depay is therefore expected to earn a recall and play against 11th-placed Watford in the central position he has occupied before at PSV Eindhoven.
The 21-year-old Netherlands international has not featured in a Premier League game since being replaced at half-time during United's 3-0 defeat at Arsenal at the beginning of October.
Depay's lack of form in a wide position has given Jesse Lingard the chance to establish himself in United's side with the 22-year-old also earning his first call-up to the senior England squad for their friendly against France.
Lingard -- who scored his first Premier League goal to help United beat West Bromwich Albion 2-0 in their last game and move within two points of joint league leaders Manchester City and Arsenal -- didn't win a first cap but warranted his inclusion, according to van Gaal.
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The Dutchman added: "I am very pleased but it is very fast, although it is the circumstances also. But I have congratulated him with his promotion.
"It is always fine to see how players are developing and because of that he is rewarded.
"I have done the same. When I think a player deserves it I have selected younger people in my period as national coach.
"It always depends on the circumstances and what kind of player you need in your selection.
"Of course it is fast but when a player shows at a high level what he can do, then he can do it also in a national team.
"Now he has the experience of being selected in the national squad of England, which is a different environment.
"Now he already has the first experience so when he is called up the next time he is more experienced, which is good."
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