With the new Premier League campaign starting on Saturday, United have landed a significant blow before the first ball has even been kicked after Dutch star van Persie decided to snub City in favour of a move to Sir Alex Ferguson's team.
When big-spending City snatched the title in sensational fashion on the final day of last season, scoring twice in stoppage-time to win against QPR, it seemed there had been a changing of the guard in England's top flight.
City, who start their title defence against Southampton at Eastlands on Sunday, had looked favourites to cement their status as the country's new superpower by signing van Persie.
But Ferguson's powers of persuasion tempted van Persie to United and Ferdinand believes it could prove a defining moment for both clubs.
"The manager has always said to me that the transfer window isn't always about who you bring in but it's as much about shaking up the changing room. And I think that's definitely something that's going to happen this time," Ferdinand said.
"Expectations here are higher than anywhere else in the world, some do brilliantly and some don't fare quite so well. I've got no worries about Robin, though.
"I know his main aim won't be a selfish one, it will be all about winning trophies. And if he can score goals like he did last year then we'll all be smiling come the end of the season."
Van Persie and fellow new signing Shinji Kagawa could both feature in United's starting line-up at Everton as Ferguson's team look to make a strong start after finishing without silverware for the first time since 2005.
Even without van Persie, City are likely to pose the biggest threat to United's hopes of winning a 20th league title.
City boss Roberto Mancini has been frustrated by his club's failure to deliver top-class signings to build on last season's first title for 44 years, but in Carlos Tevez he has a revitalised player capable of causing serious damage to Premier League defences.
Tevez spent most of last season in self-imposed exile after a touchline row with Mancini following his refusal to come on as a substitute in a Champions League tie.
He returned to play a cameo role as City won the title and with the benefit of a full pre-season under his belt, the Argentine forward looks back to his very best, scoring a superb goal to cap a fine display in last weekend's Community Shield win over Chelsea.
"I'm returning feeling renewed," Tevez said. "I'm really up for having a great season. I'm better now and only thinking about playing football.
"I feel useful and valued and that is fundamental for me. It's been a long time since I've scored a goal like that (against Chelsea), like the ones I used to score when I was at Boca, and this speaks of the confidence I have."
Chelsea appear the only other serious contenders for the title, but even the European champions have questions to answer following the exit of Didier Drogba.
Drogba was a talismanic figure as Chelsea salvaged a turbulent season by winning the Champions League and FA Cup, but the Ivory Coast striker has departed to China, leaving Fernando Torres as boss Roberto Di Matteo's leading forward.
Torres will be supported by new playmakers Eden Hazard and Oscar, who arrived for a combined £60 million.
But Di Matteo, whose side open at Wigan on Sunday, won't have been pleased to hear Torres reveal his torment at playing a bit-part role last season.
"At times I was thinking 'I will sit here on the bench, I won't make any noise. I don't even want to play'," Torres said.
On Saturday, there will be plenty of focus on Arsenal's new strikers Olivier Giroud and Lukas Podolski as the post-van Persie era starts against Sunderland, while Brendan Rodgers takes charge of his first Premier League match as Liverpool manager at West Bromwich Albion.
Fixtures (1400GMT unless stated)
Arsenal v Sunderland, Fulham v Norwich, Newcastle v Tottenham (1630GMT), QPR v Swansea, Reading v Stoke, West Brom v Liverpool, West Ham v Aston Villa
Man City v Southampton (1500GMT), Wigan v Chelsea (1230GMT)
Everton v Man Utd (1900GMT)