Hernandez was only playing due to the injury crisis at Real, but after missing several chances the striker proved to be the European champions' match-winner as he settled a feisty encounter at the Santiago Bernabeu.
The Mexico international was on hand to apply a simple finish after being set up by Cristiano Ronaldo to ensure Real beat Diego Simeone's side for the first time since winning the Champions League final in Lisbon last May.
Spanish champions Atleti had not lost to their neighbours in seven matches this season, but were made to pay for showing a lack of ambition over two legs and their task was not helped when Arda Turan was shown a second yellow card 14 minutes from time.
The tie looked destined for extra time until Hernandez took centre stage, finally popping up with the solitary goal over two legs as Real stayed in the hunt for a Champions League and La Liga double.
Hernandez made only his seventh start for Real, while Dani Carvajal, Fabio Coentrao and Raphael Varane also came in with Gareth Bale, Karim Benzema and Luka Modric injured and Marcelo suspended.
Atleti striker Mario Mandzukic was passed fit to lead the line, while Saul was preferred to captain Gabi in midfield and Miranda returned to the starting line-up.
Hernandez was presented with an early opportunity to mark his rare start with a goal, but fired a poor finish wide of the near post from a tight angle.
Ronaldo then dragged a left-footed strike off target as Real enjoyed plenty of possession, but Atleti were typically well organised and hard to break down.
Jan Oblak made a string of saves to frustrate Real in the first leg and the Slovenia goalkeeper made another fine stop to thwart Ronaldo a minute before half-time when the Portugal forward was sent clear after Mandzukic had been dispossessed.
Real had been lacking the sort of incisive passes that Modric usually provides, but Hernandez could have no complaints with the service when Isco picked him out with a sublime pass and he blazed a shot wide of the far post three minutes after the break.
There was a nervous moment for the home side when Turan went down under pressure from Sergio Ramos, playing in midfield, but there did not appear to be any contact and referee Felix Brych waved play on.
Ramos then made his presence felt at the other end when he rose well to meet Ronaldo's cross, but planted a powerful header straight at Oblak.
Raul Garcia replaced the in-form Antoine Griezmann and the substitute was left holding his head when he was shown a yellow card that ensures he will miss Atleti's next European match.
And referee Brych brandished another significant yellow card 14 minutes from time in the direction of Turan, who caught Ramos late and was given his marching orders having already been booked.
Oblak came to Atletico's rescue yet again when he came out to narrow the angle and make a fine save to deny Hernandez after the striker had turned Diego Godín sharply.
Hernandez was not to be denied, though, finally scoring the only goal over the two legs by sweeping home with his right foot from inside the area after Ronaldo had teed him up.
