Despite a hard-earned 1-1 draw with fierce rivals Atletico Madrid on Saturday, which kept them atop La Liga, the evening was marred by injury concerns. Full-back Lucas Vazquez was forced off in the final ten minutes due to injury.
Further tests have confirmed a hamstring strain, ruling the 33-year-old out of Tuesday's match at the Etihad Stadium.
"After undergoing medical examinations today, Lucas Vazquez has been diagnosed with a muscle injury in his left hamstring and will not be included in the squad for the trip to Manchester," the club announced.
Vazquez has primarily played as a winger but has been filling in at right-back since Dani Carvajal's season-ending injury in October.
Federico Valverde may step in at right-back in midweek, but the latest injury exacerbates Real Madrid's defensive woes, as Eder Militao, Antonio Rudiger, and David Alaba are also unavailable.
In Saturday's match, midfielder Aurelien Tchouameni partnered 21-year-old Raul Asencio in central defense, and the pair may continue in that role against Manchester City.
On the other hand, Pep Guardiola's squad saw the return of Ruben Dias after a three-game absence due to an adductor issue. The Portuguese center-back played the first half of City's 2-1 win over Leyton Orient on Saturday, helping the Citizens' recover from a surprising deficit to avoid an upset against the League One side.