OBJECTIVE: To investigate the joint effect of free fatty acid (FFA) and the triglyceride-glucose (TyG) index on the prognosis of overweight and obese coronary artery disease (CAD) patients. METHODS: A total of 5,887 patients were enrolled in this study. Restricted cubic spline analyses were used to assess the dose-response relationship of FFA and TyG with major adverse cardiovascular and cerebrovascular events (MACCE). Mediation analysis was used to examine whether TyG mediated the association between FFA and MACCE. Kaplan-Meier survival curves were used to compare the cumulative incidence of events. Multivariable Cox models were used to explore the independent association between Low-/High-FFA and Low-/High-TyG on outcomes. RESULTS: FFA and TyG were independent predictors of MACCE. TyG mediated 10.7% of the association between FFA and MACCE. Patients with high FFA and TyG levels exhibited a markedly higher MACCE risk (adjusted hazard ratio: 1.951, 95% confidence interval: 1.533-2.484; P < 0.001), with a significant interaction between FFA and TyG. Among patients with elevated FFA levels, MACCE increased progressively across higher TyG tertiles ( P for trend = 0.001). CONCLUSIONS: FFA and the TyG index independently predict adverse outcomes in overweight or obese CAD patients, with the TyG index mediating the relationship between FFA and MACCE. Their combined assessment enhances the risk stratification in this population.