Swindon striker Vincent Pericard had the first and last word on Tuesday night against a club for whom he played a solitary game during a 2008 loan spell from Stoke.
Pericard stretched to spectacularly volley Swindon into a first-half lead from striker partner Charlie Austin's cross.
After enduring a spell of pressure Swindon broke devastatingly to gain the insurance of a second as Austin swept in Kevin Amankwaah's teasing cross.
Swindon keeper David Lucas was rarely tested and only had to extend himself in the first half to tip round a Rickie Lambert shot and the Swindon keeper also did well to cling on to a rasping free-kick from the Saints striker.
Saints caretaker boss Dean Wilkins saw substitute Lee Barnard sent off within minutes of coming on and Pericard completed Southampton's night of misery by touching home the third from close range in injury time.