Second-half goals from Presnel Kimpembe and Kylian Mbappe made PSG the first French club to win at the Theatre of Dreams and inflicted United's biggest ever home European defeat, having never previously been beaten by more than one goal.
If Ligue 1 success is a given, with the Parisians once again running away with things at the top of the table, Thomas Tuchel's debut campaign at the Parc des Princes will be judged on how far his side progress in Europe.
Unai Emery was sacked after a couple of failed attempts at ending PSG's European hoodoo, seeing his side dumped out at this same stage by Real Madrid 12 months ago, a year on from crashing out in incredible circumstances to Barcelona.
Boasting the likes of Mbappe, Edinson Cavani and Neymar in their ranks, albeit with Cavani and Neymar currently sidelined, far more is expected of the French giants than another early exit. Not since 1994-95 have they reached the semis.
Thankfully for Tuchel, his side's two-goal win at Old Trafford has them on the brink of reaching the quarters, with the manner of the victory very much laying down a marker.
PSG have lost just one of their last 16 Champions League games at home, winning 10 of those, but that solitary defeat came in the round of 16 last season against Madrid.
They were also held to a 2-2 draw on home soil by Napoli in the group stage this time around, either side of wins over Red Star Belgrade and Liverpool as they progressed through as Group C winners, two points better off than the Reds.
In fact, none of the last six English sides to face PSG in the French capital has won. The only English team to prevail away from home versus PSG were Jose Mourinho's Chelsea in September 2004, winning 3-0 that day.
Tuchel's side also have the ability to score goals for fun, racking up 35 in their last 10 Champions League home games. One thing to note, though, is that they have not kept a clean sheet in any of their last five such matches.
That may provide United with a glimmer of hope, knowing that if they score the first goal on Wednesday the game will have a completely different feel to it. However, no club has ever progressed to the next round of the Champions League after losing the first leg of a knockout match at home by two or more goals (34 previous cases).
Recent form in Champions League: WDDWWW
Recent form (all competitions): WWWWWW
The odds are massively stacked against United as they fly out to Paris, but a look at their form since Ole Gunnar Solskjaer succeeded Mourinho in December means that they cannot be completely written off.
Saturday's dramatic 3-2 win over Southampton at Old Trafford made it 13 wins, two draws and one defeat - to PSG - in 16 matches under their caretaker manager.
United have achieved the 'minor miracle', as Mourinho put it, of making up the gap on the top four in the Premier League. With nine games to go in the English top flight, the Red Devils are well positioned to qualify for next season's Champions League.
Solskjaer has also guided his side through to the last eight of the FA Cup, overcoming Arsenal and Chelsea away en route, so even a last-16 exit from the Champions League would surely not be enough to dent his hopes of landing the job full time.
Since suffering their only defeat in the past three months in the reverse meeting with PSG, United have returned to form by overcoming Chelsea, Crystal Palace and Southampton, while also playing out a creditable 0-0 draw with Liverpool.
That well-earned point against the then-leaders came at a cost, though, as United lost three players to injury in the first half, further depleting their squad ahead of this huge showdown with the French champions.
If that was not bad enough, Alexis Sanchez limped off against Southampton at the weekend and is now expected to miss up to two months, while Paul Pogba is suspended for this return match after picking up a red card three weeks ago.
Once considered a heavyweight on the continental stage, United have won only one of their last 10 Champions League knockout games, losing six of those, with that victory coming against Olympiacos in March 2014. Their last away win in the knockout stages, meanwhile, came eight years ago against Schalke.
Taking the 2-1 loss to Valencia into account in their final group game - a costly defeat as it turned out as top spot was there for the taking in Group H - the Red Devils have lost their last two European matches. They have not lost three games in succession in the competition since March 2005.
Yet it is in these high-profile away fixtures that United have been at their best under Solskjaer. Another massive performance is required in midweek if they are to pull off a famous result.
Recent form in Champions League: DLWWLL
Recent form (all competitions): WLWDWW
United are likely to be without 10 first-team players for Wednesday's match at the Parc des Princes, including influential midfielder Pogba as a result of his late, and needless, sending-off three weeks ago.
Scott McTominay and Andreas Pereira have been given a run in the side, with the latter producing one of his best displays in a United shirt by scoring one and setting up another in the second half against Southampton.
The loss of Sanchez to injury, joining Anthony Martial, Juan Mata and Jesse Lingard on the sidelines, could see Diogo Dalot recalled in attack after featuring on the right of a front three against Palace last week.
Marcus Rashford has enjoyed a good goalscoring return under Solskjaer, but he has scored only one goal in his last nine Champions League games, six of those being starts, with that coming in United's last away match against Valencia in December.
In terms of the home side, Tuchel is still without injured attackers Neymar and Cavani, so Mbappe will continue to lead the line in their absence.
Tuchel has adapted by using three players behind Mbappe, and it may well be a case of going with the same XI that started the first leg.
Mbappe has found the net in six of his seven Champions League appearances against British clubs - six goals in total - and has scored 14 goals overall in the Champions League, which is two more than any other player has netted as an Under-21 player in the history of the competition.
Paris Saint-Germain possible starting lineup:
Buffon; Kehrer, Silva, Kimpembe, Bernat; Verratti, Marquinhos; Nkunku, Draxler, Di Maria; Mbappe
Manchester United possible starting lineup:
De Gea; Young, Smalling, Lindelof, Shaw; McTominay, Fred; Dalot, Pereira, Rashford; Lukaku
Head To Head
Incredibly, last month's reverse fixture was the first time that these two European powerhouses have faced off in a competitive match.
PSG have won three of their six two-legged knockout ties against Premier League clubs, although the most recent one ended in defeat against United's local rivals Manchester City in the 2015-16 quarter-finals.
That second leg is also the last Champions League match in which Paris failed to score, finding the net in all 23 matches since.
We say: Paris Saint-Germain 2-1 Manchester United (4-1 on aggregate)
PSG's last two European campaigns have ended at this stage, at the hands of Barcelona and Real Madrid, while United have failed to make it past the last 16 since 2013-14. Further disappointment is to come for one of these clubs, and on the basis of the opening 90 minutes it looks as though the Red Devils will be left licking their wounds.