La Liga leaders Barca opened up a 14-point advantage over Madrid thanks to second-half goals from Luis Suarez, Lionel Messi and Aleix Vidal – the second and third coming after a red card for Dani Carvajal.
Zidane selected Mateo Kovacic ahead of Isco, claiming he did so with the aim of limiting Messi's influence on the match.
"I have to make decisions. The idea was to keep an eye on Messi, and Mateo did well. We made a decision and that's it," the Frenchman told beIN SPORTS, before further discussing the issue in his post-match media conference.
"I'm making decisions as a coach. The decision was Kovacic on the pitch and Isco on the bench at the start. Then, because of how the match went, I was not able to use Isco.
"I had to use Nacho [Fernandez] because of the red card and had to changes left with one player less. That changes the game.
"I'm the coach and it's always going to be like that while I'm here.
"I will not regret anything. If you score in the first half the match is different. I know I will take the criticism, but that's football, and it will not change how I think.
"I make these decisions and I accept what happens."
Having seen the gap to the summit increase as Madrid's defence of their La Liga crown was dealt a severe blow, Zidane issued a rallying call to his players.
"People might think the league is over, but I do not and neither does [Ernesto Valverde]," he said.
"We will keep doing our work because it has not been a bad year."