Isco rose above the defence to head in a cross from Marcelo with just four minutes remaining to deliver the three points to Carlo Ancelotti in his first game in charge of Los Blancos.
Before the 21-year-old struck, the game had looked to be heading for a stalemate after Betis took an early lead through Jorge Molina, which was then cancelled out by Karim Benzema.
Afterwards, Real coach Carlo Ancelotti said: "We did everything we could. I said to the players that the first match is never easy. We played well in pre-season and we are excited. We didn't play well, but that's normal. The most important thing is to win the match, and I think we deserved to win because we created many opportunities to score. Honestly, Betis played well. They are a good team."
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