Ryan Giggs's side could salvage European football from a dire season if they win and Spurs lose to Aston Villa on Sunday, while the Saints are guaranteed to finish eighthSouthampton and Manchester United in the Premier League as they prepare to wrap up contrasting campaigns at St Mary Stadium.
The Saints started the season in magnificent form and, despite a wobble that saw them go winless for six matches, Mauricio Pochettino's team recovered their poise impressively and are guaranteed to finish eighth.
That equals the club's best finish in the Premier League era and means that the likes of Adam Lallana, Luke Shaw and Rickie Lambert are firmly in the mix for a place in England’s World Cup squad.
The price of their success could be felt at the end of the season and Southampton fans will hope that it is not the last time that they see Shaw turn out for them, with United leading Chelsea, Manchester City and Tottenham in the race for the left-back.
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If a transition of sorts is possible at Southampton over the coming months, then a full-scale one will start in earnest for Manchester United at full-time on Sunday.
Ryan Giggs is set to serve as interim manager for the final time and may also conclude a 23-year playing career with the Red Devils. The 40-year-old made his first playing appearance of his managerial reign, and possibly his last on home turf, when he came on as a second-half substitute in Tuesday's 3-1 win over Hull City.
Visiting goalkeeper Eldin Jakupovic failed to read the script when he pushed the Welshman's late free kick out of the top corner and Giggs must find the net at St Mary's if he is to retain a proud record of scoring in every season of his decorated professional career.
If Giggs does call time on a period that has made him an Old Trafford institution, he will not be the only senior player moving on.
Nemanja Vidic will sign off before joining Inter, while fellow defensive stalwarts Rio Ferdinand and Patrice Evra are out of contract. Additionally, a number of those under contract at Old Trafford may ultimately pay the price for their part in a disappointing title defence.
Soon-to-be-confirmed new manager Louis van Gaal is faced with the prospect of a significant rebuilding job after David Moyes's ill-fated reign but, nevertheless, Giggs might be credited with unearthing a pair of gems to play a part in this new era - one that will begin with a place in the Europa League if Tottenham lose to Aston Villa and United win on the south coast to pip the Londoners to sixth place.
Youth products James Wilson and Tom Lawrence were handed surprise debuts against Hull and 18-year-old striker Wilson made the most of his opportunity by scoring a double.
Robin van Persie came off the bench to complete the scoring and may join Wilson in attack in what would be a first start since sustaining a knee injury against Olympiakos in the Champions League back in March.
Fellow forward Wayne Rooney (groin) remains an injury doubt, while there are fears over the World Cup participation of his England team-mate, Phil Jones, who sustained a shoulder injury in a collision with Maynor Figueroa on Tuesday.
Southampton defender Maya Yoshida (knee) remains on the sidelines along with Jay Rodriguez (knee), but playmaker Gaston Ramires (ankle) could return after a month out.