It will be a poignant evening, with both games played inside empty stadiums and marked before kick-off by a minute’s silence for the more than 40,000 people to die of coronavirus in the UK.
Both managers suffered personally during the tragic weeks that put soccer matches into perspective.
Guardiola’s mother died from COVID-19 while Mikel Arteta, who left his post as his fellow Spaniard’s assistant in December to manage Arsenal, caught the virus in March but recovered.
In many ways Wednesday’s clash is more crucial to the Gunners.
While City are 25 points adrift of runaway leaders Liverpool, Arsenal’s burst of form before the shutdown – unbeaten in eight league games – means they have pushed themselves into contention for a top five finish.
As if this Premier League season was not strange enough, City’s European ban for breaching UEFA financial rules means that instead of a top four finish claiming a Champions League spot, fifth is likely to suffice.
Arsenal are ninth but only five points behind fifth-placed Manchester United, having played one game fewer.
Even though that game is at City, goalkeeper Bernd Leno thinks the circumstances favour the Gunners.
“We can surprise City because nobody has the rhythm. I’m sure we can have a good start,” he said.
“Mikel knows every player and he knows the manager better than anyone.”
Unlike Arsenal, Villa entered the shutdown in freefall with four consecutive defeats, leaving them second from bottom. This may feel like a fresh start though and a win over the Blades would see Dean Smith’s side jump out of the drop zone.
However, a motivated Sheffield United would reach the heady heights of fifth with a victory.