The Reds are known for making rousing second leg comebacks in European ties at home.
Ayestaran, who worked at the club under Rafa Benitez when they won the Champions League in 2006, believes a lack of supporters at Anfield will make such a comeback extremely challenging.
"Real Madrid gain a lot when Anfield is empty," he told MARCA.
"The atmosphere I experienced in the quarter-finals with Juve and in the semi-finals with Chelsea, wow, that's heavy. It pushes your team a lot.
"That game at Anfield is not easy. But Madrid have got a lot of courage from experiencing that kind of atmosphere with top players. But now they win.
"Now they have positive momentum. They have players in midfield like Casemiro, Kroos and Modric who are at the level expected of them. And that means that any element that comes into the team can do well.
"They (Liverpool) are at the opposite point, with a lot of doubts throughout the year. The absentees give them a sea of doubts."