Lionel Messi scored within three minutes of returning from injury to help fire champions Barcelona to a 4-0 home win over Deportivo La Coruna that kept them fourth, while Atletico Madrid retained top spot by thrashing bottom side Granada 7-1.
Sevilla left it late to win 3-2 at Leganes to stay third, claiming their first away win since May 2015.
Real travelled to Betis without key midfielders Luka Modric and Casemiro and captain Sergio Ramos through injury and without a win in four games in all competitions.
Raphael Varane swiftly eased the pressure on under-fire coach Zinedine Zidane by heading home Toni Kroos's floated free kick in the fourth minute.
Karim Benzema rolled home another pass by Kroos in the 31st to put Real further at ease and they went into the halftime break four goals up after a strike from returning fullback Marcelo and a brilliant breakaway finished off by Isco.
The Spain international curled in a brilliant strike in the 62nd and talisman Cristiano Ronaldo fittingly rounded off a statement of intent from the European champions by powering home in the 78th. Alvaro Cejudo had scored Betis's goal in the 55th minute.
"I'm very happy, after four draws we needed a performance like this," said Zidane.
"We played with the intensity we needed to play with, we made a strong start and when we start like we did today it's very difficult for our opponents."
In Barcelona, Brazilian midfielder Rafinha put Barca ahead in the 21st minute with the help of lax goalkeeping from Deportivo's German Lux and slid in the second goal in the 36th after the stopper failed to hold Gerard Pique's header.
Luis Suarez combined with Neymar to stretch Barca's lead two minutes before the break and substitute Messi latched on to a through ball from the Brazilian to stroke the ball high into the net in the 58th.
"Messi did not take long to make his mark on the game," said Luis Enrique, who adopted an unorthodox 3-5-2 formation for the second time this season.
"Our aim was to surprise them and it worked how we wanted it to. We created lots of chances and they created none. Deportivo have conceded very few goals this season and we got four."
Former Barcelona forward Isaac Cuenca gave winless Granada a shock lead in the 18th minute with an impressive strike but Yannick Carrasco pulled Atletico in front with goals in the 34th and 45th, completing his treble in the 61st.
"I'm very happy for Yannick, he fights every day to play like he did today," said Atletico coach Diego Simeone.
"He's very complete, he has the capacity to unbalance a game, a great shot and he has enormous potential to grow, he can be whatever he wants because he wants to listen and improve."
Nicolas Gaitan scored his first goal for Atletico two minutes after coming off the bench, netting with his first touch, and struck again in the 81st, while late strikes from Angel Correa and midfielder Tiago completed the rout.
Earlier on Saturday, a late wonder strike from Pablo Sarabia ended Sevilla's 17-month wait for an away league win.
Franco Vazquez and Samir Nasri put Sevilla in charge but quick-fire strikes from David Timor and Alexander Szymanowski cancelled out their lead, only for Sarabia to smash in from outside the area with five minutes left.
(Editing Clare Fallon)
