However, manager Gerardo Martino refused to confirm that Messi's absence would mean a first start in a Barca shirt for Neymar.
Messi has now played the 90 minutes in just one of Barcelona and Argentina's last 27 matches stretching back to when he initially picked up a hamstring strain against Paris Saint-Germain in April.
Santa Cruz spent eight seasons with Bayern Munich before playing for Premier League sides Blackburn and Manchester City.
City's Abu Dhabi-based owners opted to hire Pellegrini from Malaga as their replacement for Roberto Mancini despite the possibility of an approach for Jose Mourinho.
The midfielder will presented on July 3 after undergoing a medical. "Real Madrid and Malaga have reached an agreement for the transfer of Francisco Roman Alarcon Isco, who will be tied to the club for the next five seasons," said a statement on Madrid's website.
Since Malaga lured him away from Valencia in 2011, Isco quickly became a team leader with his passing, dribbling and goal scoring. He netted 12 goals in all competitions for the Costa del Sol side last season. Isco will now have to compete for playing time with a star-studded group of attacking players that features Cristiano Ronaldo, Mesut Ozil, and Luka Modric.
The former Valencia man will become Madrid's first major signing of the close season with Real set to pay around 30 million euros ($39 million,
Madrid are expected to spend 30 million euros ($39.6 million,
Malaga midfielder Isco has had offers from Manchester City and Real Madrid to leave the Andalusian club in the coming weeks, he revealed in comments published on Monday.
Pellegrini has more than 25 years' of managerial experience in South America and Spain and has taken Malaga and Villarreal to the latter stages of the Champions League.
Malaga produced a magnificent first Champions League campaign and were moments away from securing a place in the semi-finals of the tournament before being knocked out by two late goals from Borussia Dortmund, who ended up as beaten finalists.
Barcelona says Eric Abidal has been cleared to play in his last game with the Spanish club after recovering from a nagging leg injury.
Pellegrini, who has been in charge of Malaga since November 2010, guided the club to their highest ever league finish last season as Los Boquerones qualified for the Champions League for the first time.
The 31-year-old, now at Spanish top-flight club Malaga, has been linked with a move to Internacional, managed by Brazil's 1994 World Cup-winning captain and former national coach Dunga.
The Chilean, who led Malaga the quarter-finals of the Champions League in their first ever appearance in the competition this season, is thought to have been targeted by former Barcelona sporting director and now director of football at City, Txiki Begiristain.
Handily for Mourinho it was Albiol who got Madrid off to the perfect start as he got on the end of Luka Modric's corner to turn in his first league goal in four years with the club.
Borussia Dortmund coach Juergen Klopp admitted they had ridden their luck -- and the offside flag -- as their dramatic 3-2 victory over Malaga put them in the Champions League's last four.
Borussia Dortmund completed a dramatic comeback on Tuesday by scoring twice in stoppage time to defeat Malaga 3-2 and advance to the Champions League semifinals for the first time in 15 years.