Leading scorer Karim Benzema was the hero of the day for Madrid, finding the net twice against Villarreal - including a contentious second-half penalty - to help secure a 2-1 win and the silverware with one match to spare.
Barcelona, who won the La Liga crown in each of the last two seasons, entered Thursday's fixtures needing a win against Osasuna to have any chance of extending the title fight to the final day of the season.
Instead, they suffered a 2-1 defeat, conceding a stoppage-time goal to Roberto Torres despite playing against 10 men.
"Madrid did their own job well, did not lose any games after the break, they deserve praise," Lionel Messi said after the title officially slipped from Barcelona's grasp, according to Dermot Corrigan. "But we did plenty for them to take this league, dropping many points we shouldn't have. We have to be self-critical, starting with the players, but in all areas."
The 26-time champions are now eight league titles behind Real Madrid in their ongoing race for Spanish football supremacy.
While Barca faltered after the restart - they drew three of their first six matches after returning to the pitch - Zinedine Zidane and Co. were rejuvintaed. Real Madrid have now won 12 consecutive league matches after recovering from a slow start to the season and pouncing whenever the Catalan club slipped up in the latter stages of the campaign.
Much of the credit should go to Benzema, the much-maligned and perennially underappreciated forward who was the only scoring threat for Zidane's team at times this season.
The 32-year-old turned it on after the hiatus, scoring seven goals in 10 games - including Thursday's brace - to lead Madrid to yet another title.
Zidane, meanwhile, arguably masterminded his greatest accomplishment since taking over as Real Madrid manager, adding his second league triumph to a trophy cabinet that already includes 11 managerial titles.
He's now just three trophies shy of Miguel Munoz, the most successful manager in Real Madrid history.
"For me this is one of the best days in my professional career," Zidane said. "After lockdown and everything, it's astonishing."