United faced Villarreal in May in the final of Europe's second competition and came up short on penalties, as it was David de Gea who missed the ultimate spot-kick to confine Ole Gunnar Solskjaer's side to a heartbreaking silver medal.
But the three-time winners will have an opportunity to avenge that defeat this Autumn as they were both drawn into Group F by Chelsea legends Branislav Ivanovic and Michael Essien in Thursday's draw.
The final of the 2021-22 competition will take place in St Petersburg, Russia - the same nation that the Reds claimed their last Champions League victory back in 2008.
Back with the Yellow Submarines
Top-seeded Villarreal will of course be the primary rivals in Group F for United after their meeting earlier this year; indeed, the Reds will be seeking their first-ever win over the Yellow Submarines.
In their five previous meetings, there have been four draws and one defeat - perhaps surprisingly, all four draws were scoreless in the 2005-06 and 2008-09 campaigns of the Champions League.
Against Spanish opposition, United have faced difficulties in the past; defeated in two finals against Barcelona in 2009 and 2011 as well as being knocked out by Real Madrid in 2003 and 2013 in the knockout stages.
A tricky Italian side
United have never met Atalanta, which means a brand-new side will be making a trip to Old Trafford.
La Dea have been on an incredible journey since their promotion from Serie B back in 2010, reaching this competition on three occasions and even came within minutes of the semi-final in the 2019-20 season.
Their manager, Gian Piero Gasperini, has been likened to United legend Sir Alex Ferguson in his total dominance of his football club.
His Atalanta side are a complex tactically, with an well-rounded attack that could easily upset many opponents this year, as they have done in Serie A over the last several campaigns.
If he doesn't move on loan before the end of the transfer window, this fixture may see Amad Diallo face his former side: the winger made the move to Old Trafford in January after a transfer was agreed at the end of the 2020 summer window.
The starlet has impressed many within the United camp, getting off the mark for the first team against Atalanta's fellow Italian rivals, AC Milan in the Europa League last term. A lovely flicked header after a sumptuous ball from Bruno Fernandes gave United the equaliser in that tie.
Switzerland bound for the Reds
As their final group opponents, United will travel to Switzerland to take on BSC Young Boys, who were crowned Swiss champions last season.
The two sides have met each other only twice before, in the 2018-19 group stages of the same competition. The Reds won on both occasions, with a brace from Paul Pogba giving them the victory at the Wankdorf Stadium and a 1-0 win in the home reverse.
Young Boys have pushed three sides to the wayside en-route to the group stages after qualifying through the play-offs, defeating Slovan Bratislava, CFR Cluj and Ferencvaros.
United's chances of qualification
Overall, there should be little excuses for Solskjaer this season with a relatively fanciful group draw when there were some of Europe's big names in the first pot.
United will enjoy the chance to take on a new side in Atalanta but must be wary of their exciting football that could make their life difficult - although there were similar questions when RB Leipzig made the trip to Old Trafford last term, only for the Reds to secure a 5-0 victory.
Taking on the Swiss champions will be a great occasion for both sides but United were eliminated last season by underestimating their pot four opponents in Istanbul Basaksehir - and so United cannot make the same mistakes again.
A score of ten points usually secures qualification from the group stages, which should be more than achievable. United will also have the services of four-time Champions League winner Raphael Varane, so the experience is high at Europe's top table for the Red Devils.