The Togo international, who had been marginalized by Andre Villas-Boas, struck in each half as the north Londoners came from behind to win their third consecutive away match.
Adam Lallana opened the scoring for the hosts, swivelling on the edge of the box and rifling the ball into the bottom corner. But Spurs launched a counterattack of their own soon after, with Adebayor volleying in Roberto Soldado's sumptuous cross.
The visitors then took the lead early in the second half as Jos Hooiveld turned in Danny Rose's low cross. The advantage did not last long, though, as Lallana darted in behind the Spurs defense and set up Rickie Lambert to roll the ball into an open net.
But Tottenham's continued attacking intent under Sherwood was rewarded as Adebayor took control of a loose ball inside the box and curled a left-footed shot into the far corner that would eventually prove decisive.
Adebayor, who had fallen out of favor under former coach Andre Villas-Boas, was selected alongside fellow striker Soldado in a Spurs side showing six changes from the Portuguese's final game in charge, while Southampton brought in Lallana, Morgan Schneiderlin and Danny Fox.
The hosts initially struggled to retain possession but opened the scoring as Lallana received a pass from Fox before cleverly spinning Vlad Chiriches and placing an effort into the bottom corner from 20 yards.
Buoyed by the goal, Southampton looked comfortable and could have added a second when a flowing move resulted in Jay Rodriguez finding space in the box, only for the former Burnley man to curl his effort wide of the far post.
Tottenham capitalized, though, drawing level from a counterattack in the 25th minute when Adebayor stuck out his right boot to convert Soldado’s pinpoint cross from the left.
The visitors then operated at a higher tempo when the second period got underway, and moved ahead in the 54th minute. Neat interplay between Rose and Christian Eriksen resulted in the former delivering a low cross that was diverted home by the unfortunate Hooiveld.
Southampton was level inside five minutes. Lallana timed a run to perfection behind the Tottenham defense and, as Hugo Lloris attempted to narrow the angle, laid the ball into the path of fellow England international Lambert, who passed into the empty net.
Adebayor once again stepped up for Tottenham, however, pouncing on a loose ball from Kyle Walker's long throw to grab his second goal in the 64th minute.
Soldado missed two clear-cut chances to make the game safe as Tottenham piled on the pressure, but the spurned chances had no impact on the outcome with Southampton unable to force an equalizer. Spurs now sit six points behind leader Liverpool in seventh, while Southampton remains ninth.