Tottenham lost at home to West Ham United in the League Cup in mid-week, following the sacking of manager Andre Villas-Boas, and Sherwood saw his side fall behind against Southampton to an early goal from Adam Lallana.
Emmanuel Adebayor equalised for Spurs and a Jos Hooiveld own goal put the visitors in front, only for Rickie Lambert to draw Southampton level, but Adebayor struck again to seal the first win of the post-Villas-Boas era.
Beaten 5-0 at home by Liverpool in their last league outing, Spurs move above Manchester United to seventh place in the table, three points below the top four, while Southampton remain ninth after a sixth successive game without victory.
As he had done against West Ham, Sherwood made a bold team selection, with Adebayor partnering Roberto Soldado up front and Mousa Dembele, Christian Eriksen, Gylfi Sigurdsson and Erik Lamela playing in midfield.
Initially, Spurs struggled to get a foothold in the game, and the gaps in the visitors’ midfield were much in evidence as Lallana broke the deadlock in the 13th minute.
Danny Fox’s pass found the England international in a pocket of space between Spurs’ defence and midfield, and he cleverly shifted the ball away from Vlad Chiriches before drilling home a low shot from outside the box.
Sherwood watched the opening exchanges from a directors’ box high in the stands at St Mary’s, but having raced down to the pitch after Southampton went ahead, he saw Spurs level in the 25th minute.
Adebayor’s pass to the left sent strike partner Soldado wider than he would have preferred, but he curled in a superb cross that the Togolese striker converted with an agile airborne volley from close range.
Spurs went ahead nine minutes into the second half when Hooiveld inadvertently prodded Danny Rose’s low cross past goalkeeper Paulo Gazzaniga, but Southampton equalised just six minutes later.
Jack Cork’s incisive through ball found the excellent Lallana and he showed magnificent awareness to square the ball for Lambert, who had the simple task of rolling it into an empty net.
Spurs needed only four minutes to restore their lead, however, with Adebayor sweeping home his second goal with his left foot after the hosts failed to clear Kyle Walker’s long throw-in.
In Sunday’s other game, Everton manager Roberto Martinez visits former club Swansea City looking for a victory that will take his side into the top four.
Liverpool deposed Arsenal as league leaders on Saturday with a 3-1 win at home to Cardiff City, while Manchester City moved up to second place by winning 4-2 at Fulham.
Arsenal can return to the top of the table by beating Chelsea at the Emirates Stadium on Monday, but Jose Mourinho’s visitors will draw level on points with Liverpool if they prevail.