The Paraguayan international, who spent the last campaign on loan at Real Betis, was signed by Hughes at Blackburn Rovers in 2007 before joining him again at City two years later.
The 30-year-old has now suggested that he could play under his former boss once more as he is expected to leave the Etihad Stadium soon.
"Everybody knows that I have a big respect and I am very thankful to him for the time we worked together," Santa Cruz told Sky Sports News.
"I hope he will have a great season and achieves his goals and who knows, I want to play and I want to do good and I want to be successful so who knows we might work back together.
"I haven't spoken to him or anybody and this might be a long way to happen. A big thing to me is to be fit as I might go to a place where I will play."
Santa Cruz scored seven goals in 33 appearances for Betis last season.