The holders will demand a swift response to their chastening 5-2 home defeat at the hands of Leicester City at the weekend, while Burnley are also looking to bounce back from a home league loss.
Just three matches into the new season and already the same questions are being asked of Manchester City - most specifically their defensive frailties.
Pep Guardiola's side boasted 72% possession and had 16 shots during Sunday's showdown with Leicester, yet they still contrived to concede five goals - including three penalties - as Jamie Vardy led the Foxes' rout with a hat-trick.
The statistics make grim reading; it is the first time in 438 games at the Etihad Stadium that Man City have shipped five goals, and the first time it has happened to any of Guardiola's teams throughout his 686-game managerial career.
The criticism of Leicester's tactics from Guardiola and midfielder Rodri in the aftermath of the match, when they accused Brendan Rodgers's side of playing with 11 men behind the ball, may have been harsh, but they are likely to be faced with that proposition to an even greater extent at Turf Moor.
City's air of invincibility is still alive and well in the EFL Cup at least, and this season they are looking to become only the second team - after Liverpool from 1981 to 1984 - to lift the trophy four years in a row.
Indeed, Man City have won this competition five times in the last seven seasons and edged closer to another triumph by beating Bournemouth in the third round last week.
Burnley represent a step up in quality of opponent from that match, though, and Guardiola's ability to reflect that in his team selection is limited by a lengthy injury list which he claims left him with only 13 fit players at the weekend.
There will be no sympathy for City's plight from those at Turf Moor; Burnley have a much smaller squad of regular first-teamers, an even longer injury list and do not have the means to spend millions bolstering their ranks - as City have done with the imminent arrival of centre-back Ruben Dias.
Sean Dyche will be desperate for the club to dip their toe into the transfer market to some extent before next month's deadline, though, particularly after seeing his side lose their opening two league games.
Those defeats to Leicester and Southampton have been interspersed by progress in the EFL Cup, with the Clarets having beaten Sheffield United on penalties and Millwall to reach the fourth round.
It is already the furthest Burnley have gone in this competition since 2013-14, and if they manage to dethrone the long-standing holders on Wednesday then it would be their best League Cup showing since reaching the semi-final in 2008-09.
However, Man City have won nine and lost none of the last 10 meetings between the two sides across all competitions, including victories in the last five by an aggregate scoreline of 20-1. Indeed, Burnley have won just once against Man City in the last 24 meetings stretching back to 1974.
Burnley EFL Cup form: WW
Burnley form (all competitions): WLWL
Manchester City EFL Cup form: W
Manchester City form (all competitions): WWL
Liam Delap scored on his debut in the previous round and was also brought off the bench at the weekend, so he appears the most likely candidate to lead the line at Turf Moor.
Aymeric Laporte could be in line for his first appearance of the season, having so far been held back following a positive coronavirus test which disrupted his preparations.
Dyche could have a number of players available to him again soon, though, including James Tarkowski, who continues to be linked with a move away from the club.
Robbie Brady and Jay Rodriguez are also closing in on a return - although this game is expected to come too soon - while Ashley Barnes has been stepping up his fitness with the Under-23 side and could feature in some capacity here.
Burnley possible starting lineup:
Peacock-Farrell; Lowton, Long, Dunne, Taylor; Pieters, Benson, Brownhill, McNeil; Vydra, Wood
Manchester City possible starting lineup:
Steffen; Walker, Harwood-Bellis, Laporte, Bernabe; Doyle, Rodri; Foden, De Bruyne, Torres; Delap
We say: Burnley 0-2 Manchester City
There is usually a backlash when Man City are humbled as they were on Sunday, and Guardiola will be demanding a response from his side here regardless of how many changes he makes.
Burnley will not roll over and will have taken note of how Leicester achieved such success against Wednesday's visitors, but it is a depleted squad already and the Premier League will be their firm priority this season.