City memorably stole away the title, their first in the Premier League, with two stoppage-time strikes in their final game against QPR last season.
City's success arrived after the long-running saga involving their controversial striker Carlos Tevez.
Argentinian Tevez spent the majority of last season in his homeland after a public feud with boss Roberto Mancini before returning for City's successful late-season push.
The striker was in fine form as City won the Community Shield 3-2 against 10-man Chelsea at Villa Park last week and is set to form a dangerous pairing with compatriot Sergio Aguero.
Their partnerships could, however, stand second to United after the Red Devils closed on a deal to sign Robin van Persie before the start of the new campaign.
Last season's league top scorer was undergoing a medical on Thursday with boss Sir Alex Ferguson confident his switch from Arsenal would be settled in time for him to go straight into the squad for their Monday night opener at Everton.
That would set up the mouth-watering prospect of Van Persie joining up with Wayne Rooney - with the pair having combined for 72 goals in all competitions last season.
"We hope everything gets tied up as we hope and I am sure he will be available on Monday," Ferguson said.
"It is great to have a player of Robin van Persie's qualities to come into the squad. I am very pleased.
"In 1999 I had Dwight Yorke, Andy Cole, Teddy Sheringham and Ole Gunnar Solskjaer, the four best strikers in Europe. We are going towards that now."
The opening weekend is set to be highlighted by the debut of some big-name summer signings with European champions Chelsea set to roll out a new-look squad.
Belgium midfielder Eden Hazard will headline the new names when the Blues travel to Wigan on Sunday for a lunchtime kick-off while Fernando Torres is set to take over as first-choice striker following Didier Drogba's exit.
Arsenal will begin life after Van Persie when they host an injury-ravaged Sunderland on Saturday.
The Black Cats are without star man Stephane Sessegnon and boss Martin O'Neill sought to boost his goalscoring options by brining in free agent Louis Saha on a one-year deal on Thursday.
"Louis is a striker whose abilities have been proven at the very highest level and he brings with him a raft of experience of top-flight football," O'Neill said.
"I'm sure he will be a great addition to our squad in an area we recognise needs strengthening and I'm delighted we have been able to complete the deal ahead of our first game of the season."
Newly-prompted West Ham and Reading are both at home to start their returns to the top-flight on Saturday.
Sam Allardyce's West Ham will host Aston Villa while Reading welcome a Stoke side and Royals boss Brian McDermott has revealed he and owner Anton Zingarevich hope to emulate Stoke in their bid the stay up.
"When I first met Anton, we spoke about Tony Pulis and we spoke about Stoke and that model and how well they've done," he said.
"Not only have they survived, but they've got to an FA Cup final, they've played in Europe, they've brought in some really big players over the years.
"So, it's a really good model for us to follow."
Boss Brendan Rodgers will lead Liverpool for the first time in the league away to West Brom. Former Reds assistant boss Steve Clarke will take charge of the Baggies.
Tottenham are set to be without wantaway midfielder Luka Modric, who is reportedly set to join Real Madrid, for their late kick-off at Newcastle.
The match will be Andre Villas-Boas' return to English football after he was sacked after less than a season at Chelsea last term.
There will also be managerial debuts for Brian Laudrup, when he takes Swansea to QPR, and Chris Hughton who will lead Norwich at Fulham.
Saturday's Premier League Fixtures
Arsenal vs Sunderland
West Brom vs Liverpool
Newcastle vs Tottenham
Fulham vs Norwich
QPR vs Swansea
Reading vs Stoke
West Ham vs Aston Villa
Sunday's Premier League Fixtures
Wigan vs Chelsea
Manchester City vs Southampton
Monday's Premier League Fixtures
Everton vs Manchester United