The world's population is aging rapidly and with this demographic shift, enhancing older adults’ quality of life (QoL) becomes increasingly important. To address this challenge, it is important to explore how age-related perceptions and psychological resources impact well-being in later life. This study examined the relationship between perceived negative ageism (PNA) and QoL in older adults, with a specific focus on the mediating role of depression and the potential moderating effects of wisdom and comfort zone orientation (CZO). Using a cross-sectional design, data was collected from 554 Dutch adults aged 55 and older through the SeniorenDoenMee online study. Participants completed validated measures of PNA, depressive symptoms, wisdom, CZO and QoL. Results showed that PNA was significantly and negatively associated with QoL, both directly and indirectly through depression. Mediation analyses revealed that depression partially mediated the association between PNA and QoL. However, neither wisdom nor CZO significantly moderated the relationship between PNA and depression or between PNA and QoL. These findings highlight the detrimental impact of ageism on older adults’ well-being, underscoring the need for interventions that target both ageist attitudes and depressive symptoms.