Marcus Rashford, 18, scores on his Manchester United debut in front of the Stretford End
The Danish champions led 2-1 from the first leg and Pione Sisto increased their advantage.
Nikolay Bodurov's own goal reduced the deficit before Rashford, who only started after Anthony Martial was injured in the warm-up, struck twice.
Ander Herrera's penalty and Memphis Depay's late goal completed the rout.
Juan Mata missed a penalty at 1-1, while Midtjylland finished with 10 men after Andre Romer was sent off for a second yellow card.
Rashford to the rescue
Marcus Rashford was born in October 1997 - 16 months before FC Midtjylland were formed in February 1999
While the scoreline was emphatic in the end, United were looking at an embarrassing exit before Rashford netted twice in the space of 12 second-half minutes in front of the Stretford End.
The 18-year-old, named as a substitute on the team sheet, was only elevated to the starting line-up after France forward Martial damaged his hamstring in the warm-up.
Manchester-born Rashford showed confidence beyond his years from the start, but Sisto's tidy finish left Louis van Gaal's side staring at an embarrassing exit at the hands of a team formed in 1999.
Bodurov lifted the mood inside Old Trafford when he sliced Depay's cutback into his own net before Mata's spot-kick was saved by Mikkel Andersen after Ander Herrera was clipped by Kian Hansen.
The exciting Rashford put United ahead when he tucked home from seven yards before repeating the trick with a half-volley to make it 3-1.
Herrera added his side's fourth from the penalty spot after Hansen handled before Depay's thumping effort completed the scoring.
How's your luck
It looked like another sorry chapter in United's season of under-achievement even before a ball had been kicked.
Defender Chris Smalling was ruled out earlier on Thursday with a shoulder problem, paving the way for 19-year-old Joe Riley, a substitute in United's FA Cup win at Shrewsbury three days earlier, to make his first senior start.
Martial's injury paved the way for Rashford's debut, but after recovering from falling behind on the night, United scored four times inside the final half hour to pull away.
They could even afford to end the match with another teenage debutant on the pitch in the shape of 17-year-old Regan Poole.
Under-pressure Van Gaal managed a smile at the end after his side scored five in a match for the first time under his control in front of a 58,609 crowd.
Analysis: Doubts still remain
BBC Sport's Simon Stone at Old Trafford
Manchester United are fond of talking about their 'great' European nights. The last came against Olympiakos under David Moyes two years ago when United overturned a 2-0 first leg deficit to win 3-2. Tonight will be added to the list.
Any doubts - and there remain plenty - amongst the United fans about manager Van Gaal were set aside for the good of the team.
They stuck with them when their team went a goal down - and again when Juan Mata missed his penalty. Slight murmurings were beginning with Rashford took centre stage, and after that the decibel levels went right up.
Indeed, if supporters were writing a template for what constituted an ideal night, this would probably be it. Comeback win, five goals and a local boy becoming the hero.
Indeed, so young is Rashford - a product of the same Fletcher Moss club where Wes Brown and Danny Welbeck cut their teeth - he has become United's youngest goalscorer in Europe.
United could face Gary Neville in the last 16
The draw for the last-16 stage takes place on Friday and there is a chance United could be paired with a friendly face - as well as a bitter rival.
Liverpool and Tottenham are also through and, with no country protection, teams from the same league can be drawn against one another.
Valencia, managed by former United defender Gary Neville, are also through after a 10-0 aggregate win over Rapid Vienna
Man of the match - Marcus Rashford (Manchester United)
Rashford (centre) was thrown in at the deep end and took to the stage with ease to net twice on a dream debut.
The stats you need to know
- United have scored five goals in a European game at Old Trafford for the first time since April 2007
- Midtjylland scored with their first shot of the match
- United are unbeaten in 10 European home games
- The Danish champions have lost their last three European away games, conceding 11 in the process
Next up?
United have just two full days to recover before they entertain Arsenal in the Premier League on Sunday (14:05 GMT). The Gunners are seeking to do the double over Van Gaal's side having defeated the Red Devils 3-0 at the Emirates on 4 October.
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