French superstar Mbappe opened the scoring before the interval and then slotted home late on to inflict Barca’s first domestic defeat of the campaign after Raphinha had equalised for the champions.
Real Madrid remain third, behind Atletico Madrid and Hansi Flick’s Barca, who had won their first nine games before a chastening week.
The Catalans suffered a second straight defeat after losing on Tuesday against Paris Saint-Germain in the Champions League.
Mourinho was delighted with his team’s display in his first Clasico back at the helm of Madrid.
“My team had an extraordinary game, very organised, good concentration, with courage to play out from the back against a team that presses you a lot,” Mourinho told reporters.
“We had chances for the second goal… obviously Barca had a strong reaction but we were calm and organised and at 1-1 we never lost our tranquility.”
Barca had won six of the seven previous Clasicos since Flick arrived but were surprisingly subdued against Mourinho’s side.
“In general we didn’t have a great game, in the first half we weren’t ourselves, there were a lot of things we could have done better,” Barcelona midfielder Pedri told DAZN.
“We wanted to win the Clasico in front of our fans, but the season is very long… a league is not won here.”
Los Blancos, without suspended winger Vinicius Junior, won their fifth straight game across all competitions and are finding their footing under veteran Portuguese coach Mourinho.
After two trophyless seasons Madrid turned back to Mourinho to try and stop Barca’s dominance, and this result will give them hope they are on the right track.
The opening period of the game was cagey, with few opportunities.
Barca defender Pau Cubarsi twice reacted well to shut down Mbappe, while Real Madrid’s Marc Cucurella took a rapid liking for Lamine Yamal’s shirt, constantly grabbing at the 19-year-old winger.
Anthony Gordon, playing in his first Clasico since joining Barcelona from Newcastle, backheeled the ball to Raphinha, who fired narrowly wide as Barca threatened.
The hosts were dealt a setback when young defender Xavi Espart pulled up hurt and needed to be replaced by Alejandro Balde before the half-hour mark.
Andriy Lunin, playing in goal for Madrid after Thibaut Courtois pulled out of the squad with flu, saved at his near post from Gordon before the visitors took the lead.
Mbappe scored his 10th league goal of the season and also his easiest, with Barca’s Gerard Martin clearing a cross straight at the Frenchman, who deflected it into the net.
Barca responded by carving out a glorious chance for an equaliser but teenage sensation Yamal for once miscued in front of goal, firing wide when poised to level.
The game opened up and Yan Diomande came close to doubling Madrid’s lead before half-time, drilling into the side-netting.
Martin redeemed himself early in the second half as he held off Jude Bellingham, who could neither beat the defender nor find a free Mbappe.
Raphinha, who had a quiet first half, pulled Barcelona level just after the hour mark.
Pedri fed the Brazilian, La Liga’s top goalscorer with 13, who fired through Bellingham’s legs and Lunin could not keep the shot out.
The Ukrainian goalkeeper did make a superb save to deny Martin at a corner, as Barcelona flowed forward with the wind finally in their sails.
Yamal bent an effort wide with Lunin at full stretch and Barca substitute Frenkie de Jong had a shot desperately blocked by Dean Huijsen.
There was a sting in the tail for the Catalans though as substitute Gabriel Jesus lost possession and Madrid raced through on goal.
Eduardo Camavinga beat Cubarsi and unselfishly cut the ball back for Mbappe to tuck home his second of the night into an empty net with Joan Garcia drawn out of position.
It brought up a century of goals since Mbappe joined Madrid from PSG in 2024, although the trophies to match have not yet followed. (AFP)