The contest is perhaps no longer the must-see event it was in the late 1990s and early 2000s heyday, but it retains the legacy of those fierce battles from years gone by - some of the best in the competition's history.
The latest chapter of the rivalry takes place on Sunday, and while Manchester United have not yet re-established themselves amongst the title-chasing elite following their post-Sir Alex Ferguson slump, Arsenal are now back at the top end of the table.
Sunday's match is the Gunners' penultimate one of a season which could still see them crowned champions for the first time in 20 years, and having won the title at Old Trafford two times in the past, a positive result there again this time around will ensure that they are still firmly in the mix come the final day of the season.
However, Old Trafford has generally not been a happy hunting ground for Arsenal over the years and, despite Manchester United's struggles this term, the game is viewed as a potential banana skin which could have a huge bearing on where the Premier League trophy ends up.
With the fixture rediscovering some of its make-or-break importance, Sports Mole has undertaken the task of selecting an ultimate United-Arsenal combined XI from the Premier League era.
Goalkeeper: Peter Schmeichel
A five-time Premier League winner who joined United for just £505,000 in 1991, Peter Schmeichel established himself as a huge presence in the Old Trafford goal throughout Sir Alex Ferguson's most successful years in charge of the club.
Still the only goalkeeper to have won the Premier League Player of the Season award, Schmeichel made almost 400 appearances for the Red Devils across all competitions and, after leaving in the wake of their 1999 treble, returned to the Premier League for brief spells with Aston Villa and Manchester City later in his career.
Honourable mentions: David de Gea, Edwin van der Sar, David Seaman, Jens Lehmann
Right-back: Gary Neville
One of the fabled 'Class of 92', Gary Neville spent his entire career with United, making more than 602 appearances across all competitions and exactly 400 in the Premier League.
Never the star man in a team full of serial winners, Neville was nevertheless a key figure in eight Premier League title triumphs and went on to captain the club before retiring in 2011.
The full-back was a five-time member of the Premier League Team of the Year and, outside of domestic competition, won the Champions League twice.
Honourable mentions: Lee Dixon, Lauren
Centre-backs: Rio Ferdinand, Tony Adams
A position with no shortage of competition, we have given the nod to one player from each team at centre-back.
Rio Ferdinand became the world's most expensive defender when he joined United from bitter rivals Leeds United in 2002, but that £30m fee still proved to be a bargain with the Red Devils getting 12 years out of the former England captain.
The classy defender helped the club to six league titles and was named in the Premier League Team of the Year on five occasions during his time at Old Trafford - enough to narrowly pip his old partner Nemanja Vidic to a place in this XI.
Tony Adams, meanwhile, can lay claim to being one of the greatest captains in English football history having been handed the Arsenal armband at the age of 21 in 1988 and keeping hold of it until his retirement in 2002.
The only man to captain title-winning teams in three different decades, Adams had been in the Arsenal first team for nine years before the Premier League came into being and still went on to bring up a decade in the competition.
A one-club man who has since been honoured with a statue outside the Emirates, Adams won the Premier League in 1998 and 2002, both of which came as part of a double alongside the FA Cup.
Honourable mentions: Nemanja Vidic, Sol Campbell, Steve Bruce, Martin Keown, Gary Pallister, Jaap Stam, Kolo Toure, Steve Bould
Left-back: Ashley Cole
Ashley Cole's best years arguably came as a Chelsea player, but it is no coincidence that Arsenal's decline essentially began when he left the club for their London rivals in acrimonious circumstances in 2006.
Still reviled by most Arsenal fans, the 107-time England international was nonetheless one of the best full-backs the division has ever seen and won two league titles with the Gunners, including being part of their history-making Invincibles side of 2004.
Three of his four Premier League Team of the Year selections also came during his time at Highbury, which is enough to just about beat Denis Irwin to left-back in this team.
Honourable mentions: Denis Irwin, Patrice Evra, Nigel Winterburn
Central midfield: Roy Keane, Patrick Vieira
The two players who define this rivalry more than any other, the battles between Roy Keane and Patrick Vieira when these sides collided are the stuff of legend.
Neither gave or expected an inch and both were equally adept at picking out an incisive pass as they were at putting in a bone-shattering tackle.
Together in central midfield, it is difficult to imagine many players even reaching the all-star defence behind them.
Keane inherited the captain's armband from Eric Cantona in 1997 and went on to become United's most successful skipper ever, including winning four of his seven league titles during that time.
Vieira, meanwhile, lifted the trophy three times and was captain of the Invincibles, as well as being named the overall Premier League Player of the Season in 2001.
Between them they were named in the Team of the Year 11 times, with Keane contributing five of those and Vieira six in a row between 1998 and 2004.
Honourable mentions: Emmanuel Petit, Cesc Fabregas, Nicky Butt, Gilberto Silva, Michael Carrick
Right wing: Cristiano Ronaldo
Undoubtedly the greatest player to have graced the Premier League - if not necessarily the competition's greatest ever player - it was not until Cristiano Ronaldo left Old Trafford that he truly established himself as one of the best to have laced up a pair of boots.
The signs were very much there before his world-record switch to Real Madrid, though, by which stage his transformation from a trick-happy and sometimes ineffective youngster to the world's best was confirmed.
A Ballon d'Or winner as a United player in 2008, Ronaldo scored 118 goals in 292 appearances during his first stint with the club, helping them to three Premier League titles and the Champions League.
The Portuguese superstar went on to enjoy untold glory at Madrid and Juventus before making a sensational return to Old Trafford in 2021, adding another 27 goals and 54 games to his tally for the club.
Honourable mentions: David Beckham, Freddie Ljungberg, Bukayo Saka
Attacking midfield: Paul Scholes
Three of the Premier League's greatest-ever players battle for this coveted spot, including the majesty of Dennis Bergkamp and Eric Cantona, but we have given the chief playmaker role to Paul Scholes, who can match that pair's ability and raise it when it comes to longevity too.
One of five one-club men to make the XI, Scholes fell one short of 500 Premier League appearances and made 718 for United across his stellar 19-year career in the first team, scoring 155 goals along the way.
A master at almost every element of the game except tackling, Scholes won 11 league titles but incredibly was only named in the Team of the Year on two occasions - 2002-03 and 2006-07.
Honourable mentions: Dennis Bergkamp, Eric Cantona, Bruno Fernandes
Left wing: Ryan Giggs
The only man who can top Scholes's haul of 11 titles is his fellow 'Class of 92' graduate Ryan Giggs, who even outlasted Ferguson at Old Trafford.
The Welsh wing wizard spent his entire 23-year career at the top level with United and became one of the most decorated players in football history, helped largely by lifting the Premier League crown on a whopping 13 occasions - the same amount as Arsenal, the third-most decorated English club, have managed in their entire history.
When Giggs finally called time on his legendary career he had chalked up an unprecedented 963 appearances for United, scoring 168 goals to firmly establish himself as one of the club's greatest ever.
Honourable mentions: Robert Pires, Marc Overmars, Marcus Rashford
Centre-forward: Thierry Henry
The only problem with squeezing such a star-studded midfield into this XI is that we are only left with one centre-forward spot, and it is fiercely contested.
The likes of Wayne Rooney, Andrew Cole and Ruud van Nistelrooy are among the most deadly forwards the league has ever seen, and that is naming just three from the United side.
Despite this, one man still manages to stand out above the rest as arguably the finest ever Premier League player.
Thierry Henry was by no means an unknown quantity when he arrived in North London in 1999, one year after helping France to World Cup glory, but neither was he regarded as the deadly marksman he would become.
Arsene Wenger's decision to move him from the wing to the middle was a masterstroke and Henry soon became nigh-on unstoppable when he was on form - as United themselves discovered on more than one occasion.
No player has been named FWA Footballer of the Year or PFA Players' Player of the Year more times, no player has won more European Golden Shoes while playing in England, and he ended his Arsenal career as their all-time top scorer with 228 goals - 175 of which came in the Premier League.
Included in six consecutive Premier League Teams of the Year and a two-time Premier League Player of the Year, Henry was also twice voted in the top three of the Ballon d'Or while an Arsenal player and helped the club to two league titles, including the Invincible campaign of 2003-04.
Honourable mentions: Wayne Rooney, Ruud van Nistelrooy, Andrew Cole, Dwight Yorke, Ian Wright, Robin van Persie, Teddy Sheringham, Ole Gunnar Solskjaer