Strikes by Danny Ings and Stuart Armstrong at the start and end of the second period guided the Saints to a comfortable victory in a game in which Wolves never really seemed to get going in.
They never really provided much of an attacking outlet and threat, with them only being able to accumulate one shot on target which was kept out well by the feet of Fraser Forster.
It will be a performance that Nuno Espirito Santo will be disappointed in, especially with confidence being presumably high due to them putting in positive performances over the last two results against Arsenal and Leicester City.
Rotated side failed to do the job
Going into the game, the Wanderers made six changes from their goalless draw against Leicester on Sunday with the regular front three of Adama Traore, Pedro Neto and Willian Jose all being dropped to the bench, while defenders Conor Coady and Nelson Semedo also missed out.
This gave an opportunity for the likes of Vitinha, Morgan Gibbs-White and Fabio Silva a chance to make a case for why they should in contention to start on a regular basis.
However, they failed to do this because when going forward, the hosts were lacklustre and lacked intention as they really struggled to break down Southampton's defensive shape.
Even when Santo's regular front three were substituted on to the field in the second period, despite them looking more threatening in particular through the presence of Neto, they still didn't really present the Saints back four with anything to be concerned about.
With the number of changes that Nuno opted to make, questions have to be asked of whether he was taking this competition seriously as winning the FA Cup appeared to be their best chance of achieving European football next season.
This is because the Wanderers are currently sat in 14th position in the Premier League, 12 points adrift of the Europa League places.
Four at the back may have been more beneficial
Considering that before the clash at Molineux, Southampton had lost four consecutive games conceding 16 goals in that time, Wolves should have tried to take advantage from this by testing out Southampton's defence from the start.
Although, this is something that they failed to do as the visitors maintained dominance throughout the majority of the encounter, even when they went ahead in the 49th-minute mark.
This could arguably be put down how Santo decided to set out his side as like against Leicester he set out with a three at the back-formation.
This set up seemed to work magnificently against the Foxes because they really struggled to break down Wolves' defensive line- something which they would have planned in advance considering how much good form Brendan Rodgers side have been in this season.
However, against a side who had been undergoing a little bit of a rut consequently meaning that they would be low on confidence, a four at the back formation may have been better suited for this particular clash.
This is because it would have provided them with an extra body when they were looking to advance forward meaning that with this particular setup they would have likely provided an improved attacking threat.
On reflection bearing in mind the opponents that Wolves were facing this evening, a four at the back formation may have worked better for the Wanderers because it may have allowed them to look more threatening and dangerous when going on the attack.