The association between cystatin C and depressive symptoms in the general population has not been thoroughly elucidated to date. We investigated the association of cystatin C with new-onset depressive symptoms among individuals with normal creatinine-based estimated glomerular filtration rates (eGFR). In the China Health and Retirement Longitudinal Study, 5111 participants without depressive symptoms or renal dysfunction (eGFR < 60 ml/min/1.73 m²) were included. The outcome was new-onset depressive symptoms over 4 years, defined as a score of ≥12 on the 10-item Center for Epidemiologic Studies Depressive Symptoms Scale. The incidence risk ratio (IRR) and 95% confidence interval (CI) were calculated using modified Poisson regression models. During a 4-year follow-up period, 1746 (34.16%) incidents of depressive symptoms occurred. In a multivariable-adjusted model, the risk of incident depressive symptoms was 1.07 (95% CI 1.02–1.11) per-SD change in cystatin C. A greater cystatin C level was associated with a higher risk of new-onset depressive symptoms among subjects with relatively normal renal function.