Limited evidence exists on the combined and mediating effects of systemic inflammation on the association between insulin resistance and cardiovascular events in patients with diabetes and chronic coronary syndrome (CCS). This secondary analysis of a multicenter prospective cohort included 4419 diabetic CCS patients. Triglyceride–glucose index (TyG) and high-sensitivity C-reactive protein (hsCRP) were applied to evaluate insulin resistance and systemic inflammation, respectively. The primary endpoint was major adverse cardiac event (MACE). Associations of TyG and hsCRP with cardiovascular events were estimated using Cox regression. A mediation analysis was performed to assess whether hsCRP mediates the relationship between TyG and cardiovascular events. Within a median 2.1-year follow-up period, 405 MACEs occurred. Patients with high levels of TyG and hsCRP experienced the highest MACE risk (hazard ratio = 1.82, 95% confidence interval: 1.24–2.70,p= 0.002) compared to individuals with low levels of both markers. HsCRP significantly mediated 14.37% of the relationship between TyG and MACE (p< 0.001). In diabetic CCS patients, insulin resistance and systemic inflammation synergically increased the risk of cardiovascular events, and systemic inflammation partially mediated the association between insulin resistance and clinical outcomes. Combining TyG and hsCRP can help identify high-risk patients. Controlling inflammation in patients with insulin resistance may bring added benefits.