Former Benfica defender Lindelof was brought on as a replacement for the injured Phil Jones in the 25th minute and the hosts scored both of their goals shortly after his introduction, with United unable to claw things back despite Marcus Rashford's late goal.
Jose Mourinho's side appeared to be in control until Jones' withdrawal, but suddenly the home side turned the tables, scoring two within eight minutes of Lindelof's entrance.
Aaron Mooy netted the opener, before Laurent Depoitre added the second as he punished an awful error from United's Sweden international centre-back.
United's response was by no means emphatic, with Mourinho's men remaining devoid of craft in the final third, leaving Romelu Lukaku lacking service for most of the match.
Rashford – a half-time substitute for Anthony Martial – pulled one back for United with 12 minutes to go, but Huddersfield managed to hold on to a slender win to seal a famous day for the Terriers, who claimed their first top-flight triumph since August.
13 - Only Wayne Rooney (15) has scored more Premier League goals as a teenager for @ManUtd than Marcus Rashford. Prodigy.— OptaJoe (@OptaJoe) October 21, 2017
Proceedings were feisty early on as the two clubs clashed for the first time since 1972, with three players receiving yellow cards inside the first nine minutes and both sides going close to a goal.
The first chance fell to Lukaku, as the Belgian smashed the ball at Jonas Lossl from the edge of the box, before Depoitre failed to connect with Mooy's teasing free-kick delivery in the 16th minute.
Jones' forced substitution through injury proved a blow, with Lindelof replacing him in what was ultimately a vital moment in the match, as Huddersfield took the lead three minutes later.
Mooy was too powerful for Juan Mata in midfield and charged forward, setting Thomas Ince up for a shot which David de Gea parried away, only for the Australian to smash home the rebound.
And the Terriers got a second shortly after – Depoitre coolly skipping past De Gea and finishing into an empty net after Lindelof inexplicably left Lossl's long kick.
Mourinho responded to United's woeful first half by hauling off Mata and Martial in favour of Henrikh Mkhitaryan and Rashford at the break.
Neither had a huge impact initially, but Rashford did at least lay on United's next half chance just after the hour mark, as Ander Herrera directed his left-wing free kick wide of the target.
United certainly enjoyed the greater share of possession in the second period, but chances were difficult to come by.
Lossl was eventually forced into action again 14 minutes from the end, making a big save to push away a Herrera header.
United set up a nervy finish after Rashford latched on to Lukaku's right-wing cross and sent an unstoppable header beyond Lossl.
But it proved to be too little, too late, as Huddersfield dug deep to wrap up all three points and inflict a first Premier League defeat on United since May.
Key Opta stats:
- Jose Mourinho has failed to win all 19 Premier League games in which his side have been two goals behind (D1 L18) – that draw coming against Newcastle in September 2015 when managing Chelsea.
- This was only Mourinho's third defeat to a newly-promoted side in the Premier League (W33 D4) – losing against Crystal Palace in 2013-14, and Bournemouth in 2015-16 when at Chelsea.
- Huddersfield have beaten Man Utd for the first time in the league since March 1952, a 3-2 win in the top flight.
- Three of the last six clubs in their debut Premier League season have beaten Manchester United at home – Burnley in 2009-10, Bournemouth in 2015-16 and Huddersfield in 2017-18.
- Only Wayne Rooney (15) has scored more Premier League goals as a teenager for Man Utd than Marcus Rashford (13).
- Romelu Lukaku has either scored or assisted in eight of his last 10 Premier League games (eight goals, two assists).
- Although, the Belgian has failed to score in 18 of his last 25 Premier League games against newly-promoted teams.
- Aaron Mooy has had a hand in 10 league goals for Huddersfield in 2017 (four goals, six assists – including play-offs); four more than any other player.