In his first public comments since Guardiola announced on Friday he was taking a sabbatical, Mourinho, whose Real side are on the brink of taking Barca's La Liga crown, said the decision should be respected and even sent his adversary a hug.
"The Guardiola case is a personal decision," Mourinho told a news conference a day before Real play at Athletic Bilbao, when victory would wrap up their first domestic league title in four years with two games to play.
"It's his, he is the one who knows, he is the one who knows why, he is one who has to comment on it, he is the one who has to do what makes him happiest at any given time," the former Inter Milan, Chelsea and Porto manager added.
"I have been a coach for 12 years and for me I will be annoyed in June when I don't have any matches as I will miss training and playing, playing and training.
"But everyone is the way they are and you have to respect and accept that and hope that they really do find enjoyment because the most important thing in life is to enjoy it.
"If for him enjoying life means withdrawing from football for a while then so be it and I send him a hug."
It was an unusually conciliatory performance from the normally combative Portuguese, who has a habit of getting under the skin of the club where he was an assistant coach when Guardiola was a player in the late 1990s.
Matches between the two sides since Mourinho arrived in 2010 have often been torrid affairs, when the often sumptuous football on display has been overshadowed by brawling and accusations of refereeing bias and racist abuse.
Mourinho famously poked the man Barca have tapped to replace Guardiola, his long-term assistant Tito Vilanova, in the eye during a melee at the start of this season.
The Portuguese was asked whether Guardiola's departure, after four years and 13 titles including two Champions Leagues triumphs and three La Liga crowns, would benefit Real.
He also appeared to confirm he would stay on next season amid speculation he might leave two years into a four-year deal.
"I don't know why it would benefit us," Mourinho said.
"Real Madrid is Real Madrid, Real Madrid will continue along its own path, Real Madrid has its own decisions to make.
"My decision to continue at Real Madrid has nothing to do with who is the coach of any other team.
"It doesn't appear to me that Barcelona has people on its board of directors without talent, quite the opposite.
"If they have decided that Vilanova is the ideal person to be the next coach for sure they are doing it with conviction.
Mourinho said Real would continue to respect Barcelona as they had always done.
"Knowing with absolute certainty that next season, however much our other (La Liga) opponents improve, Barcelona will be our great rival for the Spanish title," he said.
"For us it changes nothing."
At a later news conference, Guardiola thanked Mourinho for his comments and said his decision to quit had nothing to do with the Portuguese.
"The fatigue I feel after these years is not due to Mourinho," the 41-year-old said.
"He is not even responsible for one percent. Mourinho does not tire you out, it tires you out winning so much."