It was pretty much a perfect afternoon for Atletico boss Simeone, who had lost all three derby meetings with Mourinho during his first spell in Madrid.
In fact, Mourinho had won all six of his La Liga games against Atletico between 2010 and 2013.
The first half was scrappy and Simeone and two of his defenders were shown yellow cards - including Cristian Romero, who avoided a red card after a VAR review for a foul on Jude Bellingham.
But after the break Atletico were the better team - even before Huijsen's decision to pull down Simeone's son which changed the game - and were deserved winners, ending with 18 shots to Real's eight.
This was Real's second defeat in seven La Liga games since Mourinho's return - and they already look miles off Barca - who have won all seven games and scored 31 goals.
Real Betis have the chance to overtake both Madrid teams later on when they visit Deportivo (17:30 BST).