In a game of three crisp first-time goals, Marcus Rashford - with the help of a Matt Turner howler - had cancelled out a Nicolas Dominguez strike, but Morgan Gibbs-White quickly restored the Tricky Trees' slender advantage to make it back-to-back wins for Santo.
With Rasmus Hojlund denied the chance to build on his maiden Premier League goal due to illness, Rashford led the line for a Man United attack reinforced by Antony, while Dominguez and Ryan Yates were reintroduced into the hosts' XI.
Santo's men were knocking the ball around with purpose early doors and almost benefitted from a defensive howler in the 12th minute, as Raphael Varane made a mess of a clearance after a communication error with Andre Onana, but the Frenchman breathed a sigh of relief as the ball rolled wide.
Not until the 32nd minute did a toothless Manchester United finally manage a shot on goal, but Aaron Wan-Bissaka's deflected strike presented Turner with one of the easiest saves he will ever have to make.
The right-back's tame effort was the visitors' only shot of a forgettable first half, in which Forest also had six attempts but failed to find the target with any of them, and Erik ten Hag opted for a half-time alteration in the hope of finding an attacking spark, swapping Kobbie Mainoo out for Scott McTominay.
That spark did belatedly arrive in the 55th minute, albeit from two unlikely sources, as Wan-Bissaka pulled the ball back for fellow full-back Diogo Dalot, who arrived centrally to have a pop at goal, and the Portuguese's first-time strike from 20 yards smacked the post.
The Red Devils quickly revered to old ways, though, and Forest's positive approach was eventually rewarded in the 64th minute, as ex-Man United winger Anthony Elanga slipped in Gonzalo Montiel in the right-hand side of the area, and the World Cup winner produced an exquisite turn before squaring for Dominguez to calmly pick out the far corner with a first-time finish.
Ten Hag's lacklustre troupe almost responded immediately in the 67th minute, as Bruno Fernandes's deep corner was met by Alejandro Garnacho on the volley, but the Argentine's speculative attempt bounced into the ground and onto the roof of the net.
Forest were doing a good job of marshalling Man United's attackers, but goalkeeper Turner gave the home faithful a few heart-in-mouth moments with some horrendous play out from the back, and one such misplaced pass saw him become the architect of his side's downfall in the 78th minute.
The ex-Arsenal man tried to pick out Danilo, but his pass was intercepted by a sliding Garnacho, who strode forward into the right-hand side of the penalty area and picked out Rashford, who left Turner rooted to the spot with a composed side-footed finish into the bottom corner.
However, the American redeemed himself and saw his blushes spared during a chaotic 82nd minute, as he pushed away a fierce Christian Eriksen drive and saw his side immediately launch forward on the counter-attack, which ended with Elanga laying off Gibbs-White inside the D, and the Englishman curled home a sumptuous first-time strike past a fully-stretched Onana.
Praying for a hefty chunk of added time, the Man United contingent were given a sliver of hope when 10 minutes went up on the fourth official's board, the sixth of which saw a Fernandes volley take a wicked deflection off Murillo before Turner showed brilliant reactions to tip it over.
Amad Diallo was the next to make Turner work in the eighth additional minute, but his near-post strike was meat and drink for the USA international, who then witnessed one final Eriksen attempt trickle wide before Forest's first league win over Man United since 1994 was sealed.
The hosts' second successive top-flight win has propelled them up to 15th in the standings, five points clear of the relegation zone, while the Red Devils remain seventh, nine points below the Champions League places having played an extra game.
Man United's opening game of 2024 does not take place until January 8, when Ten Hag's side travel to Wigan Athletic in the third round of the FA Cup, while Forest host Blackpool in the same round of the tournament one day beforehand.