Objective <p>Depression is an important factor affecting long-term outcomes in prostate cancer patients. Frailty and sleep quality are associated with depressive symptoms, but the pathways through which frailty and sleep quality affect depression remain unclear. The aim of this study was to investigate the relationship between frailty and depression in older Chinese patients after radical prostate cancer surgery and to explore whether sleep disturbances mediate the effect of frailty on depression.</p> Methods <p>A cross-sectional study was conducted with 277 elderly prostate cancer patients who underwent radical prostatectomy at a tertiary oncology center in Southern China (January 2022-March 2024). Inclusion criteria required ≥ 3 months postoperative recovery. Standardized instruments were administered: FRAIL Scale for frailty assessment, Pittsburgh Sleep Quality Index (PSQI) for sleep evaluation, and PHQ-9 for depression screening, supplemented by demographic questionnaires.</p> Results <p>Clinically relevant depressive symptoms (PHQ-9 ≥ 5) were identified in 18.4% (<i>n</i> = 51). Depression scores showed positive correlations with frailty (r = 0.521, <i>p</i> &lt; 0.01) and negative correlations with sleep quality (r = -0.521, <i>p</i> &lt; 0.01). Mediation analysis revealed frailty directly predicted depression (β = 0.349, <i>p</i> &lt; 0.001) and indirectly through sleep impairment (β = 0.119, <i>p</i> &lt; 0.001), with the indirect pathway accounting for 25.43% of the total effect (95% CI:0.059–0.191).</p> Conclusion <p>Elderly prostate cancer survivors exhibit heightened post-prostatectomy depression risks. Frailty acts as a dual-pathway predictor—directly exacerbating depressive symptoms and indirectly via sleep deterioration. These findings advocate for multidimensional interventions targeting frailty management and sleep optimization to improve mental health outcomes in this vulnerable cohort.</p>