Van Persie left Arsenal for Manchester United in the summer and has proved the major difference in this season's title race, taking his tally to 24 Premier League goals with Monday's hat-trick against Aston Villa.
But his appearance in north London this weekend is unlikely to go down well with the Arsenal fans who felt he had let them down by leaving in the summer.
"I don't bother about it, and I don't think Robin should bother about it either," said Ferguson.
"There was a bit of booing when he played at Old Trafford and I expect a portion of fans will do that.
"That is the modern generation I am afraid."
Arsene Wenger has confirmed this morning that United will be given a guard of honour in recognition of their championship triumph, a move Ferguson has backed.
"I am glad Arsene has done that, when they came to Old Trafford in 2002 and Sylvain Wiltord scored the only goal, we did exactly the same," he said.
"That is what great clubs should do."
However, the Van Persie element does add an extra twist, even if the Dutchman's controversial move north has now been justified.
"For Arsenal to have one of their players go to their biggest rivals of the last 20 years doesn't sit well with their fans, nor Arsene for that matter," said Ferguson.
"But it does happen. You just have to move on. Arsenal have moved on now. They are challenging for a Champions League place and have every chance of getting one.
"What it meant to Robin showed in his celebrations, not just after he had scored the goals but at the end of the match."We had a few players who were winning it for the first time but he was celebrating better than the others."
There has been a suggestion Van Persie could be joined by Robert Lewandowski at Old Trafford in the summer.
The Pole has also been heavily linked with Bayern Munich, having indicated an intention to leave Borussia Dortmund in the summer.
His pricetag will probably have gone up now though following his four-goal blast against Real Madrid on Wednesday.
"I was not surprised. I tipped Dortmund to win it the minute we were knocked out. I think they will win it now," said Ferguson.
"They all did well on Tuesday. They are a very good team.
"But Lewandowski. Four goals? What can you say? For anyone to score four goals in a game of that nature, against such a great team as Real Madrid, it is a wonderful achievement."
United's European ambitions ended in controversial fashion against Real Madrid at the beginning of March.
Now, with the league wrapped up, Ferguson must juggle his resources over the remaining four games to ensure his side remain competitive.
Having reported Jonny Evans and Michael Carrick battled through the pain barrier on Monday, both might be rested this weekend, although skipper Nemanja Vidic is expected to return after sustaining a nasty bang on the cheek against West Ham nine days ago.