The last time this matchup was played in the Premier League, United ended up sending the Saints down to the second tier of English football for the first time since the reformation of the football league in 1992.
With star striker Wayne Rooney certain to miss proceedings with a severely gashed leg (which the England man picked up last week against Fulham), it allows new signing Robin van Persie to step up to the plate and attempt to cement his place on United's first XI.
Let's face it, RVP is a world-class striker, and barring an injury—which unfortunately the Dutchman is prone to picking up—he should more than return the £24m that United staked out to bring the former Arsenal man to Old Trafford.
Whether van Persie scores tomorrow or not is somewhat irrelevant. He will work in the side, and even if he somehow fails to live up to requirements set upon him, United will always have Wayne Rooney to bang home the goals.
No, where fans of the Red Devils should really turn their attention, is toward the continued success of the Kagawa-Cleverley partnership in the centre of United's midfield.
With Paul Scholes now on the brink of retirement...again...it is crucial that United's new Japanese signing and their very promising young starlet can combine as well as they did against Fulham to carve out chances and break down the Southampton defence.
These players, both aged just 23, are very much the future of the club.
Some fans were critical of United's lack of further additions to the centre of the midfield this season.
However, with Carrick destined to return to midfield duties sooner rather than later, the trio can forge out one of the most lethal partnership from any side this campaign—both in attack and defence.
One cannot expect Shinji to get involved too much in defensive duties, and the same in regard to Carrick on the attack, but together the three will boss the midfield and have the potential to lead United to Premier League glory once again.
There is little doubt that at the end of either this or next year's Premier League season, United will be forced to bring in a new DM to replace the void that will eventually be left by Michael Carrick's departure.
For now, though, United fan's will be hoping that the two 23-year-olds can reproduce the same form that they showed in the first half against Fulham tomorrow, and set up a goal or two for RVP and United.
We could be looking at two future United greats.
Follow me on Twitter: @Eddie_Edmonds.