In a Meadow Lane thriller, Southampton became the third club from a higher division to fall to the Magpies.
Having won at Crystal Palace and Middlesbrough, Notts set off at a high tempo and were rewarded with a goal as early as the 13th minute.
It was delightfully set up by Ian Ross and Junior Mendes for central defender Michael Edwards to flick the ball home.
Notts continued to have the better of it despite some dangerous breakaways by the Saints and a second home goal a minute before half-time was crucial.
The best Notts move of the night was started by a brilliant interception by Stephen Hunt before Andy Parkinson's guile out-witted the visiting defenders.
He turned the ball back to Jason Lee on the edge of the area and he struck it sweetly into the bottom corner.
Far from sitting back, Notts went searching for a third goal on the resumption.
David Pipe and Parkinson both went close before Southampton were only rescued by a goal-line clearance which denied Edwards his second and County's third.
It was the signal for Southampton to raise their game only to find the Notts defenders superbly marshalled in front of Saul Deeney.
However, on only his fourth appearance of the campaign, Deeney pulled off a remarkable 67th minute double save to the despair first of Rudi Skacel and then Grzegorz Rasiak.
The Southampton bombardment continued and they won no fewer than 11 second-half corners, but Notts continued to prove too tough to break down and their victory adds to those of the two earlier rounds.