Cognitive Reserve (CR) plays a protective role in neurological and acute/chronic diseases. Its effect on mood, however, is still unclear, although it may be relevant in a hospital setting. We aimed to explore the relationship between CR and depressive mood in older inpatients, evaluating possible gender- and age-related differences. This study involved 86 inpatients aged ≥65 years with an MMSE ≥15. Participants underwent a multidimensional evaluation that included the assessment of CR with the Cognitive Reserve Index questionnaire, divided into three sections (Education, Working Activity, and Leisure Time). Depressive mood was assessed with the 15-item Geriatric Depression Scale (GDS). The relationship between CR and GDS was evaluated by multivariable linear regressions. Significant inverse associations between CR and GDS scores emerged in the total sample (β = -0.03 [SD = 0.02], p = .047), especially in men (β = -0.05 [SD = 0.02], p = .005) and in individuals aged <85 years (β = -0.07 [SD = 0.03], p = .01). Among the single CRI sections, CRI-Leisure Time was significantly associated with GDS in the total sample, in men, and participants <85 years. CR seems to be inversely associated with depressive mood in older inpatients. This relationship is particularly marked for CR related to Leisure Time, which may be modifiable even in older age through social support and interaction.