〔Abstract〕 To systematically evaluate the association between serum indirect bilirubin (IBIL) levels and the risk of stroke incidence in patients with cardiovascular-kidney-metabolic (CKM) syndrome stages 0-3. Methods A total of 48,301 participants with CKM syndrome stages 0-3 were included, during which 2,904 stroke events were recorded. A prospective cohort study design was employed. Cox proportional hazards regression models were used to analyze the relationship between IBIL and stroke risk, and restricted cubic spline (RCS) regression was applied to examine the dose-response relationship. Threshold effect analysis was conducted to identify potential inflection points in nonlinear relationships. Results Multivariable Cox regression analysis showed that in the overall population, each 1 μmol/L increase in IBIL level was associated with approximately a 1.2% reduction in stroke risk (HR = 0.988, 95% CI: 0.979–0.996, P < 0.05). A significant interaction was observed between IBIL and CKM stages in relation to stroke risk (P-interaction < 0.05). In individuals with stages 0–2 of CKM syndrome, higher IBIL levels showed a significant inverse association with stroke risk (P-trend < 0.05); however, no such association was observed in stage 3 patients. RCS regression and threshold effect analysis further revealed a nonlinear relationship between IBIL levels and stroke risk in stage 3 CKM patients (P-log-likelihood ratio < 0.05). When serum IBIL exceeded 10.980 μmol/L, each 1 μmol/L increase was associated with approximately 5.7% increase in stroke risk (HR = 1.057, 95% CI: 1.009–1.107, P < 0.05). Conclusion The protective effect of serum IBIL against stroke exhibits a significant CKM stage-dependent pattern, with its predictive value varying based on individual metabolic status.