Friday's play-off draw has pitted the Premier League side with the little club that has taken the game in Denmark by storm since introducing methods based on the "Moneyball" model first employed by American baseball team, the Oakland Athletics.
The strategy relies less on traditional scouting methods than statistical analysis, or 'sabermetrics', developed by Oakland's general managers Sandy Alderson and Billy Beane.
Beane, who once said "it's all about evaluating skills and putting a price on them", became the subject of a best-selling book "Moneyball" by Michael Lewis, which was turned into a film starring Brad Pitt.
Midtjylland's majority shareholder Matthew Benham, a former hedge fund manager and professional gambler, who also owns English club Brentford, is a disciple.
Since he bought into the Danish club in 2014, they have had the most successful period in their history, becoming national champions for the first time last season and beginning the new campaign as league leaders with a 100 percent record.
The one disappointment was to be eliminated from the Champions League on Tuesday with defeat on the away goals rule by Cypriot side APOEL.
That has led to a visit in a fortnight to Southampton's St Mary's Stadium, which holds almost three times as many as Midtjylland's modest 11,800-capacity ground.
Benham, meanwhile, was so determined to employ the same methods in England that he even allowed successful and popular manager Mark Warburton to leave Brentford because he did not believe in them.
At the time, the Championship (second tier) club, who came close to reaching the Premier league last season under Warburton, said their new recruitment structure would use "a mixture of traditional scouting and other tools including mathematical modelling".
If Midtjylland overcome Southampton, who are enjoying their first European campaign for 12 years, they will be through to the group stage of the Europa League.
Their previous best performances in European competition were winning 1-0 at Manchester City in 2008-09 in the UEFA Cup and reaching that competition's second round six years earlier.
Before that, however, Koeman must concentrate on the Saints' opening two Premier League games of the season -- and recovering from a ruptured achilles tendon sustained in a training session.
(Reporting by Steve Tongue, Editing by Ian Chadband)
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