Stuart Armstong had put Saints into an early lead, but Hugill came off the bench to spectacularly lob Gavin Bazunu and end the Millers' five pointless away trips this season.
Saints had been revitalised by two wins in a week and put in a blitzkrieg of attacking intent as they bombarded the Rotherham goal with 12 first-half shots.
For the second home match in a row, it took just two minutes for Southampton to take the lead as Armstrong followed up after Che Adams had hit a post to tap in from a yard.
It was the Scotland midfielder's second goal of the week, but it was in stark contrast to the rocketed free-kick he bagged against Stoke on Tuesday night.
Kamaldeen Sulemana gave Dexter Lembikisa a torrid time in the early stages. Having easily beaten the defender, the winger forced Viktor Johansson into a fine save before the Ghanaian cut back to Adam Armstrong to scuff a goal-bound shot.
The hosts thought they had doubled their advantage in the 16th minute after Adam Armstrong had skilfully backheeled in Kyle Walker-Peters' cross - only for the offside flag to keep the score 1-0.
Millers manager Matty Taylor is under pressure following just one win so far this season and attempted to find a foothold in the match by hooking Fred Onyedinma after 30 minutes and switching to a back three.
Adams forced another good save out of Johansson from a header before the striker attempted an acrobatic shot, but was blocked by Lee Peltier.
A medical emergency at the end of the first half in the home end did not immediately stop play, but delayed the beginning of the second half by almost 15 minutes.
Saints monopolised possession again after the interval but failed to continue the blizzard of shots - with Jan Bednarek's header a rare test for Johansson.
Johansson was forced into his best save of the match with 20 minutes to go, when a well-worked Saints move saw the keeper keep out Will Smallbone's shot from point-blank range.
The home side's failure to take their chances came back to haunt them in the 74th minute as Hugill produced a stunner for his third goal of the season.
The second-half substitute watched a loose defensive header bounce before carefully lifting over a stranded Gavin Bazunu. It was the Millers' first shot on target and just their second in total.
They came close to a second goal five minutes later as Oliver Rathbone scampered off the left to force a save out of Bazunu.
A low near post save denied Carlos Alcaraz and Jan Bednarek was thwarted on the line as Saints failed to find a winner despite having 80 per cent of possession.