Casemiro and Jesus Vallejo were both absent for Madrid through suspension, while captain Sergio Ramos missed out with a hamstring problem once again. Zidane did shuffle his pack, though, with Raphael Varane, Marcos Llorente, Luka Modric, Vinicius Junior and Federico Valverde all coming into the XI.
William Carvalho was the game's best player in the early stages as Betis started well, with the visitors causing a number of problems in the final third of the field.
Giovani Lo Celso - Betis's leading scorer this season - headed an Andres Guardado free kick towards the Madrid goal in the 18th minute during a strong spell of pressure, but Keylor Navas was on hand to make a smart save.
Madrid's fans had to wait until the 23rd minute for their team to register their first attempt - the strike came from Marcelo, but the Brazilian's effort was always moving wide of the post.
Marc Bartra then forced Navas into a smart save down the other end of the field as the former Barcelona centre-back looked to register at the Bernabeu.
Madrid had a golden chance to take the lead in the 34th minute when a mistake at the back from Betis presented Karim Benzema with a shooting opportunity, but the Frenchman struck the post before Lo Celso forced Navas into another smart stop down the other end moments later.
Betis continued to cause problems late in the half and had another excellent chance in the 38th minute when Junior Firpo found himself free inside the Madrid box, but the left-back somehow headed over the crossbar.
Madrid's build-up was still far too slow at the start of the second period, but Benzema did break into the Betis box on a couple of occasions in the 10 minutes after half time.
Vinicius then forced Pau Lopez into a smart save just before the hour as Los Blancos started to offer more of a threat in the final third of the field.
Madrid were perhaps fortunate to keep all 11 men on the field in the 58th minute, meanwhile, with Dani Carvajal bringing Junior to the deck when the left-back appeared to be through on goal.
Betis made the breakthrough in the 61st minute, however, when a wonderful pass from Lo Celso released Guardado, whose far-post cross was turned into the back of the net by Loren for his sixth league goal of the campaign.
Vinicius curled wide of the far post as Madrid looked to hit back in the period that followed, but there was still no sign of Gareth Bale, with Marco Asensio the first player off the home side's bench.
Navas had to make another wonderful save in the 68th minute to keep out a curling Lo Celso strike, however, at the end of what was a brilliant move from the away side.
Betis doubled their advantage in the 75th minute, though, and it was another excellent team goal as Jese turned a low Junior cross into the back of the net from close range.
There was to be no potential farewell appearance from Bale, however, with Lucas Vazquez the third player off the Madrid bench, and the huge speculation surrounding the Wales international's future will continue.
Betis continued to chase more goals in the latter stages with the visitors quicker and slicker than their off-colour opponents on the afternoon.
As it turned out, the match came to an end with a 2-0 scoreline, leaving Madrid with plenty to ponder as the European champions prepare to spend big this summer with the view to a more prosperous 2019-2020 campaign.
REAL MADRID (4-3-3): Navas; Carvajal, Varane, Nacho, Marcelo; Valverde (Isco 69'), Llorente, Modric; Brahim (Asensio 60'), Benzema (Lucas 77'), Vinicius
REAL BETIS (5-3-2): Pau; Francis, Mandi, Feddal, Bartra, Junior; William (Sidnei 91'), Guardado, Kaptoum (Jese 68'); Lo Celso, Loren (Tello 74')