Manuel Pellegrini will take charge of his first Champions League game since joining the away side, with several key players set to be recalled after a rest on Saturday.
The Premier League side's two previous ventures into Europe's elite club competition saw it crash out in the group stages, finishing third in 2011-12 and bottom last season.
Manuel Pellegrini takes charge of his first Champions League match since replacing Roberto Mancini at the helm at the Etihad Stadium.
His side has hardly enjoyed ideal preparation for its first foray into Europe this season, however, after being held to a 0-0 draw by Stoke City on Saturday.
After resting several of his stars at the Britannia Stadium, Pellegrini is likely to return to a more familiar lineup against Plzen, with Sergio Aguero, Jesus Navas and Fernandinho all in line to play from the start, and he could also be boosted by the return of captain Vincent Kompany, who has been battling a groin problem and has traveled with the squad.
For its part, Plzen heads into the competition in superb form, having won all six of its qualifying matches.
The team also tops its domestic league table after an unbeaten start consisting of six victories and two draws.
The home side - which will likely look to its top scorer in qualifying, Marian Cisovsky, to provide the goal threat - will undoubtedly start as an underdog.
With City picking up just the one away win in six in the Champions League to date, coupled with the fact that Plzen has only failed to triumph in one of its previous 11 home matches in Europe, the club will retain some hope of an upset.