Arsenal also advanced to a second consecutive FA Cup final to soften the blow as Chelsea moved 10 points clear of Arsene Wenger's side in the league standings.
Here is a look at Europe's major leagues on Saturday:
Chelsea's Eden Hazard bolstered his player-of-the-year credentials with his 38th-minute goal that halted third-place United's six-game winning run. If Chelsea wins at Arsenal next Sunday, Jose Mourinho's side can secure the title with four games to spare with a victory at Leicester on April 29.
As Arsenal's hopes of a first league title since 2004 took a further hit, the FA Cup holder did clinch a place in a second successive final. Alexis Sanchez scored twice as Arsenal beat Reading 2-1 after being forced into extra time by the second-tier club.
West Bromwich Albion moved eight points from danger after beating Crystal Palace 2-0.
Leicester climbed off the bottom by beating Swansea 2-0, Burnley dropped to last place by losing 1-0 at Everton, and Southampton lost 2-1 at Stoke.
Messi set up Luis Suarez's first-minute opener then notched his 400th goal for Barcelona in stoppage time to give the Spanish league leaders a hard-fought 2-0 win over Valencia.
Ronaldo made up for a missed a penalty by likewise scoring in injury time to reach the 50-goal mark for a fifth consecutive season as Real Madrid beat Malaga 3-1 at home to stay two points behind Barcelona with six rounds left.
Madrid's win proved costly with both Gareth Bale and Luka Modric picking up injures four days before it hosts Atletico Madrid in their second-leg Champions League quarterfinal with the tie poised at 0-0.
Athletic Bilbao's Aritz Aduriz also struck two goals to lead its 4-0 win over 10-man Getafe after Emiliano Velazquez was red carded for fouling the striker with only the goalkeeper to beat.
PSV Eindhoven sealed its 22nd Eredivisie title and dethroned four-time defending champion Ajax when it beat SC Heernveen 4-1.
The title ended a seven-year drought for PSV, and earned it a place in next season's Champions League.
Luuk de Jong gave PSV a dream start by heading in a Luciano Narsingh cross in just the third minute. Memphis Depay double PSV's lead with a 20-meter free kick before Joey van den Berg pulled a goal back for Heerenveen just before the half hour.
De Jong restored PSV's two-goal cushion before halftime with another header, and PSV's fans began celebrating their title early in the second half. Narsingh completed the scoring shortly before fulltime.
Borussia Dortmund's new-found inspiration led to a 3-0 win over Paderborn while Bayern Munich closed in on the Bundesliga title with a 2-0 win at Hoffenheim.
It was Dortmund's first game since Juergen Klopp announced on Thursday his end-of-season departure after seven years at the club.
Sebastian Rode's 38th-minute strike and an own goal from Andreas Beck in injury time were enough for Bayern to move another step to claiming the title. Bayern could wrap it up next weekend if Wolfsburg loses to Schalke on Sunday.
Also, Bayer Leverkusen routed Hannover 4-0 to move to third. Mainz won 3-2 at Freiburg, Hertha Berlin drew 0-0 with visiting Cologne, and Augsburg beat struggling Stuttgart 2-1.
Juventus took another important step towards the Serie A title as it eased to a 2-0 win over second-place Lazio.
Lazio midfielder Danilo Cataldi was sent off late on for a dangerous tackle on Tevez.
Juventus moved 15 points clear of Lazio.
Sampdoria was held 0-0 by relegation-threatened Cesena.
Paris Saint-Germain showed it can cope with injuries and without top scorer Zlatan Ibrahimovic as it won 3-1 at Nice to pressure Lyon in the close-fought French title race.
PSG was one point ahead of Lyon with six games remaining. Lyon can reclaim top spot if it beats bitter rival Saint-Etienne at home on Sunday, but will have played one more game than PSG.
Third-place Monaco lost ground as it conceded a last-minute goal in a 1-1 home draw with Rennes.
Reims defeated Bastia 2-1 to move three points above the relegation zone.
Guingamp was held to 1-1 at home by Evian, while Metz downed last-place Lens 3-1.
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