Steve Howard's 14th goal of the season maintained Derby's six-point lead at the top of the Coca-Cola Championship table - but it required a much-improved second-half performance.
The Rams were completely dominated in the first period at St Mary's Stadium, where Southampton should have been comfortably ahead at the interval.
But Derby weathered the storm and extended their winning sequence in all competitions to eight games, the last five by 1-0 with Howard the match-winner in three of them.
Another indication of Derby's superb form was that they inflicted a first league defeat on Southampton in nine outings and their first at home since September.
The Saints gave their new on-loan Polish striker Marek Saganowski his debut and he made an instant impression, forcing Stephen Bywater into a fine save from the first attack of the match.
Two minutes later the 28-year-old, borrowed from French club Troyes, fired over and as Saints enjoyed much the better of the early stages, Bywater was troubled by an inswinging corner from Inigo Idiakez.
Grzegorz Rasiak, with his international colleague alongside him, was off target on three occasions before Colombian midfielder Jhon Viafara hit the crossbar and Rudi Skacel failed to convert the rebound.
Derby's complete inability to gain a foothold prompted their manager Billy Davies to make a tactical change as he sent on Gary Teale in place of Bob Malcolm to introduce more width, and at least it resulted in a first goal attempt as Stephen Pearson shot wide, albeit from long range.
The substitution also stemmed the tide, but the visitors knew they had to improve significantly in the second period if their excellent run of results was to continue.
After the interval there was no repeat of Southampton's flying start and Craig Fagan had Derby's best chance so far when he curled a right-foot effort wide in the 53rd minute, that being the striker's last act as he was replaced by Giles Barnes.
Saganowski and Skacel also made way for Bradley Wright-Phillips and David McGoldrick, but those changes failed to restore Southampton's superiority and Pearson fired over from a good position before sending a header too high from an even better opening.
Rasiak was also off target at the other end while youngster Gareth Bale, who had been linked with a move to the Premiership this week, showed glimpses of his talent with a free-kick that flew just too high and a shot Bywater held.
David Jones curled a free-kick wide for Derby, but eight minutes from time the former Manchester United midfielder was even more influential as he crossed for Howard to score the decisive goal.
Teams:
Southampton Davis, Baird, Lundekvam, Pele, Bale, Wright,Idiakez, Viafara, Skacel (McGoldrick 54), Rasiak (Dyer 77),Saganowski (Wright-Phillips 53).
Subs Not Used: Bialkowski, Ostlund.
Booked: Idiakez, Baird.
Derby Bywater, Edworthy, Leacock, Moore, Camara,Oakley (Mears 86), Jones, Malcolm (Teale 35),Fagan (Barnes 53), Pearson, Howard.
Subs Not Used: Michael Johnson, Lupoli.
Booked: Howard, Fagan, Barnes.
Goals: Howard 83.
Att: 27,656
Ref: J Moss (West Yorkshire).