The Spain worldwide nearly joined Madrid in August 2015, but signed a fresh four-year deal with United the following month.
The goalkeeper has been heavily linked with a move to Real Madrid yet again with Spanish club monitoring De Gea for years.
"I can guarantee that he's not going this season, and it is my feeling it will be very hard for him to go", Mourinho told reporters.
'And my feeling is it will be very hard for him to go'. For me, he's the best in the world, so I want to keep him here at United.
In the previous five head to head records between Real Madrid and Manchester United, Manchester United have won two matches and two matches won won by Real Madrid and another match ended in a draw.
And when they face off in Santa Clara at Levi's Stadium - the clubs last met on US soil in a 2014 friendly, when a crowd of more than 109,000 in Ann Arbor, Michigan, watched United win 3-1 - it will be just over two weeks until they meet again in the UEFA Super Cup in Skopje, Macedonia. It has been alright - I'm getting into it better and better every day.
When the two teams halted play after 30 minutes for a hydration break in the baking heat in Santa Clara, Mourinho headed straight for Real keeper Keylor Navas as he walked towards the touchline before shaking the Costa Rican's hand.
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He said: "You have contacts, you have feelings, you understand things".
And Mourinho insists Gareth Bale was not a summer target, saying it would be "mission impossible" just like a move for Cristiano Ronaldo. It was clear that Bale likes Madrid, likes the situation and is in a club with a very good situation now.
"Obviously we want more consistency in his talent".
In his pre-match press conference, Jose Mourinho confirmed that Sergio Romero and David De Gea will each play 45 minutes in the game against the Galacticos. The players are in pre-season, and the managers and owners are not happy if you talk about them.
"If the club has no chance to give me the four players, then (so) be it".
The former Tottenham player was only involved for 45 minutes at the Levi's Stadium but on three occasions he found team-mates with passes which, if they had been a bit sharper, they might have profited from.
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