United suffered defeat in last season's final to remain on 12 cup successes down the years, compared to 13 for rivals Arsenal who are out in front.
Unai Emery pulled no punches in the build-up to Arsenal's meeting with Chelsea in the Premier League last weekend, admitting that anything less than victory for his side would effectively spell the end of their top-four challenge.
This first season at the Emirates Stadium was never going to be about challenging for the title for Emery. Instead, the Spaniard is targeting a return to the Champions League and silverware in one of the cup competitions.
With Arsenal exiting the EFL Cup to Tottenham Hotspur last month, the FA Cup and Europa League provide the North London outfit with their only other opportunities to add a trophy to the cabinet.
Emery did not exactly field a strong side for the round-three tie at Blackpool, but nor did he have to. Joe Willock netted a couple of first-half goals at Bloomfield Road and Alex Iwobi rounded off a straightforward 3-0 win late on.
This visit of United will be a far tougher test, of course, and Arsenal will be expected to field something close to their strongest possible XI, with nearly a full week's rest heading into the game.
Emery's men have a good record in this competition against fellow Premier League clubs, winning 12 of their last 13 such meetings - the only defeat in that time coming at home to Watford in 2015-16.
The stars may well align should Arsenal come out on top this Friday, as they have gone on to win the FA Cup in the previous three seasons that they have knocked out Man United – the fifth round in 2002-03, in the final in 2004-05 and in the quarter-final in 2014-15.
Recent form (all competitions): DLWWLW
While stats can often be deceiving, in this instance they tell the full story. Man United have played seven matches under Ole Gunnar Solskjaer and won seven, compared to two wins in Jose Mourinho's final eight matches at the helm.
The recovery process is in full swing and, following last week's 2-1 win against Brighton & Hove Albion, the Red Devils are now three points behind the top four.
United have closed the gap on Arsenal in recent weeks with their six successive league wins, drawing level on points with their historical rivals, and they face sides sitting 16th, ninth and 19th in their next three games.
Interim boss Solskjaer has brought the feel-good factor back to Old Trafford during his first month at the helm thanks to the wins over Cardiff City, Huddersfield Town, Bournemouth, Newcastle United, Tottenham and Brighton in the league, as well as seeing off Reading in the third round of the FA Cup.
Nineteen goals have been scored across those seven matches and four goals conceded - a vast improvement on the the results that preceded Solskjaer's return to the Theatre of Dreams.
It means that United still have something to fight for in the Premier League, with fourth place their target over the remaining four months, and they are also fighting for honours in the FA Cup and Champions League.
Next month's blockbuster Champions League last-16 clash with Paris Saint-Germain could well be a classic, but for now all focus is on progressing in the FA Cup, a competition that Solskjaer won twice in his playing days.
United do not tend to crash out at this stage, doing so only once in their last 14 fourth-round ties - against Liverpool in 2011-12 - and they now have another chance to show what they are capable of when given the freedom to play their own game.
Recent form (all competitions): WWWWWW
Solskjaer hinted last weekend that Alexis Sanchez will make his return to action on Friday against his former club, but the man he swapped places with at Old Trafford - Henrikh Mkhitaryan - is likely to miss out.
Alexis's return has come at a good time, as Solskjaer has started Marcus Rashford in each of his six league games in charge and is expected to give the Englishman a breather.
The Spanish midfielder has been involved in 11 goals in 10 FA Cup starts against Premier League opposition - three goals of his own and eight assists.
As well as being without Mkhitaryan, who has returned to training but is still not fully fit, Emery must also make do without Hector Bellerin - the right-back picking up a serious knee injury against Chelsea that will keep him out for up to nine months.
The German playmaker returned to the matchday squad last week but has not been used since being taken off at half time against Brighton on Boxing Day. This seems like the perfect opportunity to integrate him back into the side.
Arsenal possible starting lineup:
Cech; Lichsteiner, Mustafi, Sokratis, Monreal; Guendouzi, Xhaka; Willock, Ozil, Iwobi; Lacazette
Manchester United possible starting lineup:
De Gea; Young, Bailly, Lindelof, Shaw; Herrera, Matic, Pogba; Mata, Lukaku, Alexis
Head To Head
These sides have met on 14 previous occasions in the FA Cup, eliminating each other seven times apiece (including final victories) - neither side has been knocked out by another team more often.
This will mark just the third time Arsenal have hosted Man United in the world's oldest club cup competition, though, with the other two matches ending in victory - 5-0 in January 1937 and 2-1 in February 1988.
The Red Devils are unbeaten in their last three meetings with the Gunners overall, winning both league matches last season and playing out a 2-2 draw at Old Trafford last month, shortly before Mourinho was axed.
We say: Arsenal 1-2 Manchester United
The sides are level on points in the Premier League and there is little between them in terms of their FA Cup pedigree. This competition has been kind to Arsenal and United down the years, but only one of them can make it through on Friday night. Even if a few changes can be expected, United are in superb form and will fancy their chances of extending their good record against the Gunners.