Having stormed to a 3-0 triumph at their home of their fiercest rivals in the cup on Wednesday, Barcelona edged to a more closely-fought win at the same venue on Saturday night to move 12 points clear of Los Blancos in La Liga and 10 above Atletico Madrid at the top of the table.
Ivan Rakitic scored the only goal of the game as Barca took another big step towards a second consecutive league title, essentially eliminating Madrid from contention in the process.
Madrid began the match looking like a team intent on avenging their defeat in the Copa del Rey Clasico, with Gareth Bale firing an early free kick over the crossbar and Karim Benzema also flashing a snapshot off target.
Marc-Andre ter Stegen made the first save of the contest after 13 minutes when the ball fell to Toni Kroos just outside the area, but his deflected drive was comfortably dealt with by the Barcelona keeper and the visitors soon began to grow into the game.
It took until the 19th minute for the league leaders to create their first chance, though, with Lionel Messi exchanging passes with Luis Suarez before holding off a defender inside the box and lifting his finish over Thibaut Courtois but off target.
Madrid responded with another opening midway through the first half as Vinicius Junior skipped past Gerard Pique down the left flank, but the Barcelona defender recovered to get back and block Luka Modric's eventual strike after Vinicius had combined with Benzema to find the Ballon d'Or winner.
It was a Croatia international on the other team that ultimately made the difference, though, as Rakitic latched on to Sergi Roberto's through-ball before producing an exquisite chipped finish over Courtois to open the scoring.
It was a major setback for the hosts in a game they had more than held their own in up to that point, and they nearly responded through an unlikely source when Sergio Reguilon fired just wide from outside the area shortly after the half-hour mark.
Barcelona ended the half on top as Messi began to have a growing influence on the game, seeing one free kick land on the roof of the net before failing to turn a follow-up effort past Courtois after the Madrid keeper could only parry Suarez's initial effort into a dangerous area.
There was a late chance for Madrid to level things up on the stroke of half time when Modric met Carvajal's headed cross with a header of his own which flew over the bar, and the opening 45 minutes ended in acrimonious style as the two captains clashed.
Messi went down clutching his face before squaring up to Ramos, and replays showed that the streetwise Madrid skipper caught his Barcelona counterpart in the face with a naughty elbow which went unseen by the officials.
The Argentine talisman was left fuming as he went down the tunnel for half time, and his mood nearly worsened when Benzema was left with a glorious chance at the back post four minutes after the restart, but the offside flag spared the Frenchman's blushes as he put the sitter wide from point-blank range.
Barca should have doubled their advantage shortly afterwards when Dani Carvajal inadvertently sent Suarez clean through on goal, but the Uruguayan - scorer of a hat-trick in the reverse fixture and two in Wednesday's Clasico - took too long over his finish and was crowded out by a combination of Raphael Varane and Courtois.
Vinicius was a regular threat for Madrid down the left flank, but as was the case in midweek it was his finishing which let him down, and he put one effort too close to Ter Stegen to spark an end-to-end period shortly before the hour mark.
Barcelona went straight up the other end and drew a save from Courtois through Ousmane Dembele, before a low cross from Alba took a deflection off Carvajal which sent it spinning narrowly wide of the far post.
Madrid responded in kind as Vinicius was almost able to pounce upon Barcelona's failure to clear their lines, but having eluded the desperate attempts of Pique to make a block he then saw Clement Lenglet throw himself in the way of his eventual strike.
Barcelona's pressure began to grow again after the hour mark as they went in search of a second goal, which Dembele perhaps should have provided when he dragged a shot wide after being picked out by Messi.
Madrid were largely limited to long-range efforts for their part, with Vinicius and Casemiro both missing the target from similar positions before Benzema drew a routine stop from Ter Stegen with a powerful 25-yard strike late on.
The introductions of Marco Asensio and Isco - the former of whom came on after Bale had been whistled off by the home fans - did add more threat to the Madrid attacks, but they struggled to turn promising situations into chances on an evening where the defences were on top for the most part.
Indeed, it was a defender that had Madrid's best chance to level things up late on when Varane nodded over in stoppage time, although the closest either side came to a second goal arrived even later as Messi curled a fine effort inches past the angle from the edge of the area.
It would have provided the perfect finale for Barcelona, but they were still able to celebrate a third Clasico success of the season and second of the week to extinguish any lingering title hopes Madrid had while boosting their own treble bid in the process.
Madrid have now lost their last three home games across all competitions, while Barcelona have won four away league Clasicos in a row for the first time in their history and now lead the head-to-head record against Madrid with 96 wins to 95.
REAL MADRID (4-3-3): Courtois; Carvajal, Varane, Ramos, Reguilon; Modric, Casemiro (Isco 76'), Kroos (Valverde 55'); Bale (Asensio 61'), Benzema, Vinicius
BARCELONA (4-3-3): Ter Stegen; Roberto, Pique, Lenglet, Alba; Rakitic, Busquets (Semedo 92'), Arthur (Vidal 71'); Messi, Suarez, Dembele (Coutinho 78')