With eight games left, Barca have an eight-point advantage over their great rivals, whom they thrashed 5-0 at the Nou Camp in November, and their run-in to the end of the season looks significantly less challenging on paper.
Real host Barca in two weeks, a few days before they clash in the King's Cup final, and then have tough away games at Valencia, Sevilla and Villarreal.
Apart from Real and fifth-placed Espanyol, Barca's other six opponents are all in the lower reaches of the standings.
Coach Pep Guardiola, who has engineered league triumphs in his first two seasons with Barca and victory over Real in all five "Clasicos" he has contested, warned against complacency after the Villarreal game and said sport was capable of producing big surprises.
"If you declare yourself champion with an eight-point lead and eight games left you can only lose the league," the 40-year-old former Barca and Spain midfielder told a news conference.
"In the end the league is only won when it is won," he added. "We have some terribly difficult matches coming up. "Madrid is always Madrid and they will fight to the end."
Barca beat Villarreal, who surrendered third place to Valencia as a result, without suspended playmaker Xavi.
Guardiola also rested joint La Liga top scorer Lionel Messi after an injury scare on duty with Argentina, only bringing him off the bench in the second half.
Spain defender Gerard Pique scored the crucial goal in the 67th minute when he controlled a Sergio Busquets flick from a corner on his chest and lashed the ball into the net from close range, sparking wild celebrations from the Barca bench.
"We got the better of the third-placed team and made them run," Guardiola said.
"We didn't have that many chances but we were more concerned with controlling the game. It was a great win."
Barca have 81 points from 30 games and host relegation threatened Almeria next weekend. Real, who play at Athletic Bilbao, have 73 points.
Both clubs are in Champions League quarter-final action midweek and if they progress to the last four will meet home and away at the end of April and beginning of May.
