Madrid was on the verge of a second consecutive draw when the Spain midfielder drilled a right-footed shot from just outside the area between goalkeeper Ivan Cuellar and his post.
Isco has been heavily linked with a move away from Real Madrid this summer after falling out of favour under Zinedine Zidane.
Sporting retook the lead five minutes into the second half as Vesga looped a measured header into the far corner.
"Zidane makes the line-ups and is carrying the squad in an extraordinary way".
"[Isco] has been really great, he's quite pleased with his targets but more for the result for the team", said Marcelo.
"I have always made it clear that I want to be here for many years", he said after the win over Sporting. "We were able to pull out a win against a very hard rival", Barcelona coach Luis Enrique said.
When Real Madrid scored the third goal he played as a full back. Atletico had two penalties saved, Salvatore Sirigu making two saves in two minutes. "It is the difficulty of this job, having to leave very good footballers on the bench, but I have to make decisions".
"This Is a relief in order to score and take the three points, that was what we needed".