Montserrat Seara triggered the attack after Spanish newspaper La Region published her light-hearted remark following Benitez's appointment at the Bernabeu last month, the third time he has joined a club previously managed by his rival.
Mourinho was clearly not amused and speaking to reporters after Chelsea beat European champions Barcelona on penalties in a Washington friendly, he delivered a withering straight-faced response.
"The lady is a bit confused," he said after the match that ended in a 2-2 draw. "I am not laughing...
"Her husband went to Chelsea to replace Roberto Di Matteo and he went to Real Madrid and replaced Carlo Ancelotti.
"The only club where her husband replaced me was at Inter Milan where, in six months, he destroyed the best team in Europe at the time.
"For her also to think about me, and to speak about me, I think she needs to occupy her time.
"And if she takes care of her husband's diet, she will have less time to speak about me."
Benitez was hired by Inter Milan in 2010 after Mourinho had led an ageing team to a European and domestic treble before leaving for Real Madrid. The Spaniard was dismissed after six months, with the club down in seventh place in Serie A.
The Spaniard also managed Chelsea on an interim basis, succeeding Roberto Di Matteo in 2012, five years after Mourinho's first spell ended, when the Italian was sacked six months after winning the Champions League.
His spouse's comments appear to have rekindled a bitter feud between the two men that dates back to his time in charge at Liverpool, when he clashed with Mourinho several times between 2005 and 2007.
Defending Premier League champions Chelsea begin their domestic campaign on Sunday when they meet last season's FA Cup winners Arsenal in the Community Shield at Wembley.
However, they may go into that match without England defender Gary Cahill, who suffered a suspected broken nose when he scored Chelsea's second goal, and Spain striker Diego Costa, withdrawn due to a slight hamstring strain.
(Reporting by Steve Tongue; Editing by John O'Brien)
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