Sergio Ramos, Xabi Alonso and Angel di Maria were among those not to feature.
Of those who did though, Mesut Ozil and Cristiano Ronaldo were big enough names to get the job done against a Betis side, who came into the match still harboring European ambitions.
Ozil opened the scoring just before the break before Karim Benzema added a second after it. Jorge Molina then pulled one back from the penalty spot, and, for a while, the visitor's tails were up.
In stoppage time though, Ozil added his second of the night as Real Madrid recorded a 3-1 win.
Here are some talking points to come out of the match...
Two goals and an assist won Cristiano Ronaldo all the accolades last weekend at San Mames as Real Madrid beat Athletic Bilbao 3-0.
On Saturday evening, in the 3-1 win against Real Betis, the Portuguese forward failed to score but was still able to star.
Given Jose Mourinho's decision to rest certain players, it may have been a surprise to see Ronaldo play the whole match, but he doesn't seem the sort to ever miss out.
He almost opened the scoring in the first half.
Dashing in side and riding challenges, he managed to get a left-footed shot away from nearly 30 yards, which rattled Adrian's post.
Unselfishly, he then laid on the assist for Karim Benzema's goal and was involved in the build up for Los Blancos' third.
He tested Adrian with a free-kick from distance too and was a constant menace to the Betis 'keeper throughout the 90 minutes, registering six shots (via whoscored.com).
But, on a night where he failed to add to his 31 La Liga goals, he will perhaps be most proud of his four key passes (via whoscored.com)
Not since March 10th, when Real Madrid beat Celta Vigo 2-1, has Mesut Ozil completed 90 minutes for Los Blancos.
Before the visit of Real Betis on Saturday, he had played just 95 minutes of La Liga action in April and a further 80 in the Champions League.
So it will come as major boost for Los Blancos to see the German international not just back getting minutes but getting goals too.
Ozil came through the whole match seemingly unscathed while scoring Real Madrid's first and third goals too.
He was the heartbeat of the second goal as well, carrying the ball nearly 50 yards in the build up to Karim Benzema's effort.
Jose Mourinho will hope for more of the same when he pits him against his fellow countrymen, Borussia Dortmund, in midweek.
Not that they'd have been banking on three points at the Bernabeu, but without them, chances of finishing in the top four look a little tougher for Real Betis.
With six games to go, they're six points behind Real Sociedad—who have a game in hand—and, besides, have the task of leapfrogging Malaga and Valencia first too.
They still have to play Barcelona at Camp Nou as well.
In reality, it's probably a good thing though. They're only in their second full season back in La Liga, and the challenges that come with the Champions League would likely affect their league form.
That said, they still have a great chance of qualifying for the Europa League.
When the teams were named one hour before kickoff, there were a few eyebrows at the inclusion of Carlos Henrique Casemiro.
Casemiro is a 21 year old midfielder—capped three times by Brazil—who came to Spain in January on loan from Sao Paulo.
He has been playing for Real Madrid's B-team up until now but on Saturday evening was handed a start at the Santiago Bernabeu.
Los Blancos may decide to buy him in the summer, so it was worthwhile to throw him in and give him a further inspection before making any decisions.
Playing as part of a midfield two, alongside Luka Modric, his performance was OK.
He got stuck in, completed 87 percent of his passes (via whoscored.com) and did more than enough to suggest we may see him again before the season is out.
While many changes were made, the inclusion of Iker Casillas was not one which Jose Mourinho felt necessary on Saturday evening.
Perhaps because of some ongoing feud; perhaps because of the mixed messages it may have sent.
That wasn't so interesting in itself, but what was interesting were certain rumors which escalated during the match.
Italian journalist Tancredi Palmeri tweeted that the Real Madrid Ultras were singing anti-Casillas songs, believing him to be a negative influence in the dressing room:
During Real Madrid game, the hardest fans made chants against Casillas hinting he is the 'rat' leaking from dressing room.Never seen before— Tancredi Palmeri (@tancredipalmeri) April 20, 2013
The chants were also mentioned by the Sky Sports commentary team, but Real Madrid TV's Phil Kitromilides disputed that there was such rumblings from the home fans:
About those "chants" I am at the Bernabeu, quite near the Ultras, I speak fluent Spanish and heard nothing, so...— Phil Kitromilides (@PhilKitro) April 20, 2013
Whether there was or not, the fact remains that Iker Casillas continues to wait for his chance and, while he waits, this story will run and run.