The two will clash in the first El Clasico of the season at the Camp Nou next weekend and must also negotiate huge Champions League ties in midweek as Real host Juventus and Barca travel to face AC Milan.
A return to league action comes first though, with Madrid welcoming Malaga to the Santiago Bernabeu, whilst Barcelona are away to Osasuna.
The Catalans are sitting pretty atop La Liga, alongside Atletico Madrid, five points clear of Real having won all eight of their league games so far.
Indeed both Barca and Atletico have the chance to match Real’s league record nine wins to start the campaign from the 1968/69 season on Saturday.
And midfielder Sergio Busquets doesn’t want his teammates to lose concentration against a struggling Osasuna side with big games just around the corner.
“It won’t be an easy game for us in Pamplona, and we can’t be thinking about Real Madrid yet. One lapse in concentration could allow them to gain ground on us in the table. We cannot afford to get distracted,” he said.
“To break the league record we have to win in Pamplona and beat Real Madrid. If we can do it, we will open up a decent gap in the standings.
“Records are fine but they don’t guarantee that you’ll end the season with a trophy. We have a few points advantage over Madrid but we have to keep an eye on Atletico.”
Messi’s return after missing the victories over Celtic and Valladolid is not the only good news on the injury front for Gerardo Martino’s men as centre-backs Javier Mascherano and Carles Puyol could both feature on Saturday.
Puyol hasn’t played since undergoing knee surgery in March and Busquets underlined his importance as a leader both on and off the field.
“He’s an important figure in the dressing room.
“We’re all very happy for him. It’s clear to see that he is close to being back to full fitness and he’ll soon be fully integrated back into the team.”
Real have the chance to temporarily cut the gap at the top to two points as they play first on Saturday afternoon against an improving Malaga side.
Carlo Ancelotti’s men have been far from impressive despite winning six of their eight league games to date, thanks in large part to last minute winners away to Elche and Levante.
“Up to now we’ve had some poor games and our problems have been made worse by the fact that Barcelona and Atletico keep winning,” Ancelotti told Italian newspaper Corriere Della Sera.
“We need to play better, the criticisms are fair. The fans are demanding and they are right to be.
“As a coach I can say that in the games coming up, Malaga and Juventus at home and Barcelona in the Camp Nou, we’ll do better. At the same time we couldn’t play worse than we did against Levante and Elche.”
Although not expected to start, Bale should feature at some stage as he continues to recover from a thigh injury which kept him out of the games against FC Copenhagen and Levante.
And in an action packed Saturday, Atletico also have the chance to extend their 100 percent start to the campaign when they travel to Espanyol.
David Villa is available despite missing Spain’s recent World Cup qualifiers due to an arthritic ankle problem and he will be partnered by the prolific Diego Costa who will be looking to maintain his lead over Messi as La Liga’s top goalscorer.
Real Madrid v Malaga (1400GMT), Valencia v Real Sociedad (1600GMT), Osasuna v Barcelona (1800GMT), Espanyol v Atletico Madrid (2000GMT)
Granada v Getafe (1000GMT), Almeria v Rayo Vallecano (1500GMT), Real Betis v Elche (1700GMT), Valladolid v Sevilla (1900GMT)