The Bundesliga side's strength in depth proved the difference in Villach on Wednesday as former Real Madrid, Ajax and Milan striker Huntelaar showcased his predatory nous just before the hour.
Matip then added a second as Schalke followed up Sunday’s 1-1 draw with Besiktas with a morale-boosting victory.
Southampton had started the brighter of the two teams, Rickie Lambert testing goalkeeper Timo Hildebrand with an 11th-minute header before Lloyd Isgrove shot wide from 30 yards seven minutes later.
Jason Puncheon and Michel Bastos then spurned opportunities for the Premier League outfit before the half-time interval offered both managers the chance to make wholesale changes.
Huntelaar was the most notable Schalke player introduced, Adam Lallana the pick of the Southampton substitutes sent on.
And Netherlands international Huntelaar wasted little time in making his presence felt as he opened the scoring after 58 minutes. An initial effort from Christian Clemens was parried by Kelvin Davis and the 29-year-old pounced to fire home the rebound.
Lallana blazed over as Southampton pressed for an immediate response, but the result was put beyond any doubt when Matip doubled Schalke’s lead.
Clemens was again involved as it was from his corner that Matip capitalised on slack defending to net from close range.
