Carlo Ancelotti's side top the table on goal difference above Copa del Rey holders Betis, who like Madrid have won their first three matches of the campaign.
Madrid will play at the Santiago Bernabeu for the first time this season on Saturday as renovation work continues on their iconic ground.
Goalkeeper Thibaut Courtois, who was nominated for the Uefa player of the year prize won last week by teammate Karim Benzema, expects Betis to give them a difficult afternoon.
"Betis play really well. Last season we had some tough games against them. They play good football, they've got loads of experience and we'll have to press them well, while being careful," said Courtois.
"It's going to be a good match. Then we've got the Champions League, so I hope we can keep winning with another victory in our first home game. It'll be tough, but we'll be ready."
Madrid, the record 14-time European champions, begin their European quest away to Scottish champions Celtic next Tuesday, while Betis visit HJK Helsinki in the Europa League.
Barcelona appear to be hitting their stride, with Robert Lewandowski striking twice in each of the past two outings following a goalless draw on the opening weekend.
Having finally been cleared to make his Barca debut in the 4-0 win over Real Valladolid, France defender Jules Kounde could line up against his former club Sevilla on Saturday.
Both clubs will hope to fare better in this season's Champions League after failing to advance from the group phase last year. Barca's first assignment is against Viktoria Plzen, while Sevilla must find a way to stop Erling Haaland and Manchester City.
Atletico Madrid, Spain's fourth representative in the Champions League, go to Real Sociedad before returning home to face Porto.
Villarreal and Athletic Bilbao, who have both yet to concede a goal, aim to remain unbeaten as they take on Elche and Espanyol respectively.
PLAYER TO WATCH: BORJA IGLESIAS
The chief catalyst behind Betis' impressive start, Iglesias has four goals after scoring in each of his club's first three matches -- wins over Elche, Mallorca and Osasuna.
The 29-year-old spent much of his early career with the Celta Vigo reserves before a successful loan spell at Real Zaragoza in 2017-18 brought about a move to Espanyol.
He struck 17 times in his first full season in the top flight, catching the eye of Betis who paid 28 million euros for him -- the club's most expensive transfer since forking out what was then a world-record fee for Denilson in 1998.
After netting just three goals in his debut season with Betis, Iglesias bagged a combined 32 goals in all competitions over the past two years, and has begun the new campaign in style.
KEY STATS
7 - years between La Liga wins for Almeria, who earned their first top-flight victory last weekend since relegation to the second division in 2015.
262 - League goals scored in Europe by Edinson Cavani, who has joined Valencia on a two-year deal. The Uruguayan notched 112 goals in Serie A across spells at Napoli and Palermo, 138 for Paris Saint-Germain in Ligue 1, and 12 with Manchester United in the Premier League.