Ronaldo's sixth-minute goal from a clever Kaka assist was his 28th of the season in the league, putting the Portuguese forward five clear of Barca's World Player of the Year Lionel Messi at the top of the scoring chart.
Santander, who are 18th in the standings, were reduced to 10 men six minutes before the break when the referee ruled defender Domingo Cisma had handled the ball for a second time in the game and showed him a second yellow card.
Real doubled their lead in added-time when a dinked Karim Benzema effort was deflected over the line by Santander defender Bernardo under pressure from Sergio Ramos.
Substitute Angel di Maria, back after injury, netted the third goal and the best of the night in the 73rd minute when he powered a left-foot strike past goalkeeper Tono from just outside the area.
Benzema's deflected effort made it 4-0 a minute from time to seal an 18th win for Jose Mourinho's side in 19 league matches since the end of September and lift them to 61 points from 23 games.
"The best thing is that we have three more points and one less game to play," Mourinho told a news conference.
"We won without sparkle, but without much effort," the Portuguese added.
"At this stage of the season, winning without suffering and without much effort is the most positive thing."
With Real in such imperious form and unlikely to drop many points, world and European champions Barcelona's bid for a fourth straight domestic title already appears a lost cause.
Benzema said the comfortable win was ideal preparation for the Champions League last-16 first leg at CSKA Moscow.
"It was a great game for us tonight and now we'll try to do the same on Tuesday," the French international told Spanish television.
In the earlier kick-off, Espanyol climbed above Levante into the fourth Champions League qualification place despite surrendering the lead in a 1-1 draw at Getafe.
Sevilla ended a run of three straight defeats and eight games without a win when they beat Osasuna 2-0, a first success for new coach Michel.
Gary Medel netted the opening goal in the 16th minute at the Sanchez Pizjuan when he crashed a low shot into the corner of the net before substitute Piotr Trochowski turned in the second in second-half added-time.
The victory lifted the Andalusian club to 10th on 29 points as they seek to get their bid to qualify for Europe next season back on track.
Osasuna, who beat Barca 3-2 at their Reyno de Navarra stadium last weekend, are eighth on 31 points.
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