Background <p>Although social isolation, sleep duration, and frailty have each been linked to depression, their potential sequential pathway—from social isolation through sleep duration and frailty to depression—has not been examined in a large, nationally representative Chinese sample. Guided by the stress–vulnerability model, this study aimed to investigate whether sleep duration and frailty sequentially mediate the association between social isolation and depression.</p> Methods <p>Data from the 2018 CHARLS wave were used. Key measures included a general information questionnaire, social isolation index, sleep duration, frailty index, and CESD-10. Spearman’s correlation was first used to explore the associations among social isolation, sleep duration, frailty, and depression. Subsequently, a chain mediation analysis was conducted using the PROCESS macro in SPSS to examine the mediating roles of sleep duration (first mediator, M1) and frailty (second mediator, M2) in the relationship between social isolation (independent variable, X) and depression(dependent variable, Y).</p> Results <p>The final analytic sample consisted of 5270 older Chinese adults, with a median age of 67 years (interquartile range [IQR]: 64–73); 47% were women. Pearson correlation analysis showed that social isolation was negatively correlated with sleep duration (<i>r</i> = -0.061, <i>p</i> &lt; 0.01), positively associated with frailty (<i>r</i> = 0.138, <i>p</i> &lt; 0.01), and positively associated with depression (<i>r</i> = 0.162, <i>p</i> &lt; 0.01). Mediation analysis indicated that sleep duration (indirect effect = 0.065, 95% CI: 0.035 to 0.098), frailty (indirect effect = 0.497, 95% CI: 0.388 to 0.607), and their chain pathway (indirect effect = 0.050, 95% CI: 0.027 to 0.074) significantly mediated the relationship between social isolation and depression.</p> Conclusion <p>Promoting sleep health and identifying frailty in older adults may reduce depression and improve mental health.</p>