La Liga leaders Barcelona tumbled to an embarrassing 1-0 defeat at Almeria on Sunday, failing to capitalise on Real Madrid's derby draw with Atletico to extend their advantage
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.