City and United are understood to be ready to make a bid for the Spain international if the LaLiga club decide to sell him in the summer.
Madrid are set for a large squad overhaul in the summer following a disappointing season.
Zinedine Zidane wants to bring in a host of new players meaning that several will have to leave the club to make room.
Spanish publication Sport have reported that Manchester City, Manchester United and Paris Saint-Germain would be happy to take Isco.
The 27-year-old was out of favour with Santiago Solari prior to his sacking and has made most of his Madrid appearances from the bench this season.
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The LaLiga giants paid around £27million for the midfielder in 2013 from Malaga and he has since gone on to make 277 appearances for the club.
He has also helped them to four Champions League titles during his time at the club.