The Arsenal boss spent three-and-a-half years at the Etihad Stadium serving as a coach under esteemed tactician Pep Guardiola before the former Gunners captain was lured back to north London back in December 2019.
Since then, the Spaniard has locked horns with Guardiola and City on numerous occasions with mixed results. However, all previous meetings pale in comparison to Wednesday night's seismic showdown, which will have major repercussions in the Premier League title race.
Manchester City, the red-hot favourites, are bidding to retain their domestic crown and claim a fifth title in six years. For Arsenal, who failed to even qualify for the Champions League last year, participation in the title race is a most unexpected - albeit welcome - surprise.
Arsenal have faltered in recent weeks and are now just five points ahead of City, who have two games in hand. But even if the Gunners fail to overcome Manchester City - both in the title race and on Wednesday night - then their progress under Arteta has still been nothing short of sensational.
It wasn't that long ago that the Gunners boss was on the receiving end of some scathing criticism from fans and pundits alike over controversial selection decisions - including tweets from Match of the Day host Gary Lineker following the decision to exile former Emirates favourite Mesut Ozil. The call did not go down well in some quarters - and it was Arteta who took the fall.
After Ozil broke his silence over his Arsenal exile, Lineker appeared to side with the former Real Madrid man, claiming that it was "soul-destroying" to be denied the opportunity to play football.
And Lineker went one further a couple of months later when Arsenal were thrashed by Man City in the Carabao Cup quarter-finals back in December 2020 by mischievously quipping: "It’s getting increasingly more difficult to blame Mesut Ozil."
Few people, if anybody, will be cracking jokes at Arsenal or Arteta's expense on Wednesday night, though, regardless of the result.
He made a similar call when he decided to strip Pierre-Emerick Aubameyang of the Arsenal captaincy midway through last season due to disciplinary issues. And although a dearth of striking options ultimately cost them in their bid to crack the top four, Arsenal are now reaping the rewards of his decision to weed out underperforming highly-paid players like Ozil and Aubameyang in favour of hungry, young stars.
The Gunners may yet come up short against Guardiola and City, but their renaissance has been one of the feel-good stories of the season and has given the neutrals a title race that they wouldn't have necessarily had otherwise following implosions at the likes of Liverpool and Chelsea.
Arteta's fingerprints are well and truly all over a club that is finally back where it belongs. And he could yet have the ultimate last laugh by ending Arsenal's 19-year title drought next month.