The season begins on Saturday with Tottenham Hotspur hosting Liverpool in an early kickoff between two other new managers and continues later with a northeast derby between Middlesbrough and Newcastle United.
However, the big guns are not in action until Sunday, when champions Arsenal face Everton at Goodison Park and their two main title rivals meet at Stamford Bridge for the showcase opener to 2004-05.
Mourinho's first competitive game since guiding Porto to the Champions League trophy in May looks like a baptism of fire against the country's most successful club for the past decade.
No manager has more experience of the English top-flight than United's Alex Ferguson and no-one has less than Mourinho.
However, the confident Portuguese coach has the advantage of facing an FA Cup-winning side that will be punching well below their weight thanks to injuries, suspension and Olympic duties.
Dutch striker Ruud van Nistelrooy, Portugal winger Cristiano Ronaldo and England defender Rio Ferdinand are among the absentees, while the season of Norwegian forward Ole Gunnar Solskjaer is probably over before it even started.
Chelsea have only minor worries for Sunday, when they should unveil more new faces after Roman Abramovich's spending topped $350 million since he took over the club last July.
DROGBA DANGER
Record signing Didier Drogba should lead the charge up front, possibly with another new striker in Serbian Mateja Kezman.
While points do not matter too much in August, both sides know the psychological value of victory in a season-long
Unbeaten last season, Arsenal will be missing skipper Patrick Vieira, still linked with a move to Real Madrid, and defender Sol Campbell through injury.
Manager Arsene Wenger will not expect the distraction to weigh heavily, given the way his side beat United 3-1 in last weekend's Community Shield without the France midfielder.
Prolific striker Thierry Henry, promising Spaniard Jose Antonio Reyes and a fit-again Robert Pires should cause problems for an Everton side who could face a relegation fight.
Everton manager David Moyes will be without teenage forward Wayne Rooney, who is still recovering from breaking a bone in his foot during England's Euro 2004 defeat by Portugal.
White Hart Lane will have two new faces in the dugouts, with Spurs' French coach Jacques Santini and Liverpool's Spanish boss Rafael Benitez making their managerial debuts in the Premier League.
Michael Owen, like Vieira linked with Real Madrid, should play alongside newcomer Djibril Cisse after the England striker was rested from Liverpool's midweek Champions League qualifying win at Graz AK.
Up in the northeast, Newcastle United skipper Alan Shearer, in his final season before retirement, is set to play his 500th league game in the Tyne-Tees derby.
By contrast, his new Dutch strike partner Patrick Kluivert is set for his very first taste of English football.
The hosts should field their new strike force of Mark Viduka and Jimmy Floyd Hasselbaink, backed by fellow newcomer Ray Parlour and Spain's Gaizka Mendieta, in an early test of Boro's potential.