Purpose: To explore the association between apathy and health-related quality of life (HRQoL) from resident and proxy perspectives and whether cognition and depression moderate this relationship. Methods: Secondary analyses with baseline data from a cluster randomized trial on the effects of a care program for depression in Nursing Homes (NHs) were conducted. For HRQoL, the Visual Analogue Scale (VAS) and the Dutch version of the European Quality of Life (EQ-5D) were administered to 521 NH residents, and to professional caregivers reporting from the perspective of the NH resident (Resident–Proxy) and from their own perspective (Proxy–Proxy). Utility scores (U) were calculated for the three perspectives. Apathy, depression, and cognition were measured using the 10-item Apathy Evaluation Scale, the Cornell Scale for Depression in Dementia, and the standardized Mini-Mental State Examination, respectively. Results: Mixed models adjusted for clustering within NH units revealed that apathy was negatively associated with HRQoL both from the Resident–Proxy perspective (EQ-5D VAS: estimated effect, − 0.31, P < 0.001; EQ-5D Utility: − 0.30, P < 0.001) and from the Proxy–Proxy perspective (VAS: − 0.29, P < 0.001; U: − 0.03, P < 0.001), but not from the Resident–Resident perspective (VAS: − 0.05, P = 0.423; Utility: − 0.08, P = 0.161). Controlling for depression and cognition and their interaction terms with apathy did not change the results. Conclusion: Apathy is negatively associated with NH resident HRQoL as reported by proxies. Depression and cognitive functioning do not moderate this association. NH residents do not self-report a relationship between apathy and HRQoL. More research is needed to understand caregiver and NH resident attitudes and underlying assumptions regarding apathy and HRQoL.