Madrid - Barcelona's fearsome front three of Lionel Messi, Luis Suarez and Neymar could join forces for the first time in four months against Alaves, while Cristiano Ronaldo will make his Real Madrdid return on Saturday.
Neymar has missed Barca's 100 percent start to the season due to his efforts in leading Brazil to Olympic gold on home soil, but returned to Spain for the first time since May after more international duty in World Cup qualifying this week and is expected to start at the Camp Nou.
Messi is a much bigger doubt after missing Argentina's clash with Venezuela in midweek due to a groin problem.
The five-time World Player of the Year has played a limited part in training in recent days and coach Luis Enrique is likely to be cautious for the first of seven games in 22 days for Barca.
Paco Alcacer is in line to make his debut after sealing a €30 million ($33 million) move from Valencia and the Spanish international striker is aware he will have to make the most of limited opportunities as fourth choice behind Messi, Suarez and Neymar.
"I will do everything I can to take advantage of the chances I have to the full," Alcacer said as he was presented on Thursday.
Andres Iniesta has also returned to training following a knee injury and will battle Arda Turan and Denis Suarez for a place in midfield as both have impressed early in the campaign.
Ronaldo makes his long-awaited return at the Santiago Bernabeu against Osasuna earlier on Saturday in what will be his first appearance since suffering ligament damage in his left knee during Portugal's Euro 2016 final win over France.
Real haven't suffered in Ronaldo's absence with two wins from their opening two La Liga games and victory over Sevilla in the European Super Cup.
And after winning two Champions League titles in his first three seasons at Madrid, Gareth Bale insists the European champions have to put more emphasis on ending a four-year run without winning La Liga.
"It's important to try to win La Liga because it's been a few years since we have and it's normal that it's our focus," said Bale.
"I'm looking forward to next weekend's game against Osasuna and I'm sure that they will make it difficult for us, but it'll be great to be able to call upon almost the whole squad."
Karim Benzema and Pepe have also returned from injury to leave Zinedine Zidane with a fully-fit squad bar the absence of goalkeeper Keylor Navas.
Champions League finalists Atletico Madrid desperately need to kickstart their season after back-to-back disappointing draws with Alaves and Leganes when they visit Celta Vigo in the first match in a new early Saturday kick-off time of 13:00 (11:00GMT) designed to compete with the English Premier League in Asian television markets.
Celta finished sixth last season, but have also endured a poor start with defeats in both their opening matches and the Galicians will be without influential playmaker Fabian Orellana for a month due to a muscle tear.
Early season leaders Las Palmas have been on fire in scoring nine goals in their opening two games to shoot ahead of Barca and Madrid to the top of the table for the first time in 38 years.
However, the searing Spanish heat could get in their way this weekend with record temperatures for September registered across the country.
League chief Javier Tebas has promised players' safety won't be risked and Las Palmas' visit to Sevilla is one of a number of games that could be delayed or even postponed if temperatures are deemed to be too high.
Fixtures (all times GMT):
Real Sociedad v Espanyol (18:45)
Celta Vigo v Atletico Madrid (11:00), Real Madrid v Osasuna (14:00), Sevilla v Las Palmas, Malaga v Villarreal (16:15), Barcelona v Alaves (18:30)
Sporting Gijon v Leganes (10:00), Valencia v Real Betis (14:00), Granada v Eibar (16:15), Deportivo la Coruna v Athletic Bilbao (18:30)