Abstract Background Impaired cognition, poor health-related quality of life (HRQoL) and depressive symptoms are common in older patients with kidney failure. Understanding what influences HRQoL is important, as older patients regard HRQoL as a health priority. This study examines whether cognitive functioning is associated with HRQoL and whether depressive symptoms mediate this effect in older patients with kidney failure. Methods Outpatients aged ≥ 65 years from 35 Dutch and Belgian hospitals with eGFR 20–10 mL/min/1.73 m2 were included from the ongoing DIALOGICA study. Cognitive functioning was assessed using the Montreal Cognitive Assessment. Depressive symptoms were screened with 2 Whooley Questions and thereafter assessed with the 15-item Geriatric Depression Scale. HRQoL was assessed using the 12-item Short-Form Health Survey. To assess whether cognitive functioning is associated with HRQoL, cross-sectional multivariable linear regression analyses were performed. Subsequent mediation analyses were performed with PROCESS using the product method. Results In total, 403 patients were included, with a mean age of 76.5 years (SD 5.8) and estimated glomerular filtration rate (eGFR) of 14.5 mL/min/1.73 m2 (SD 3.0). Cognitive functioning was associated with mental HRQoL (adjusted β 0.30, 95% CI 0.05;0.55) but not physical HRQoL (adjusted β 0.18, 95% CI -0.09;0.44). This effect is mediated by depressive symptoms (adjusted β 0.14, 95% CI 0.04;0.25). Conclusion Lower cognitive functioning was negatively associated with mental HRQoL, which was mediated by depressive symptoms in older patients with kidney failure. Future research should explore whether cognitive interventions and treatment of depression improve HRQoL in this vulnerable patient population. Graphical Abstract