Background <p>Stroke is a major public health challenge, and the combined effects of chronic inflammation and insulin resistance (IR) on stroke require further investigation. This study used high-sensitivity C-reactive protein (hsCRP) and the metabolic score for insulin resistance (MetS-IR) to assess chronic inflammation and IR, respectively, and explored their combined effects on stroke in middle-aged and older Chinese adults.</p> Methods <p>Based on the China Health and Retirement Longitudinal Study cohort, 7,422 participants ≥ 40&#xa0;years old without stroke at baseline in 2011 were enrolled and followed up to 2020. MetS-IR was calculated from (ln 2 × fasting plasma glucose + triglyceride × body mass index)/ln high-density lipoprotein cholesterol. Participants were divided into four groups based on hsCRP (cut point 1&#xa0;mg/L) and MetS-IR (cut point 34.4). Cox proportional risk modeling and mediation analysis were used to explore the effect of different inflammation and IR states on stroke.</p> Results <p>During an average follow-up period of 8.6&#xa0;years, a total of 781 (10.5%) participants experienced a new stroke. Compared with participants with lower levels of both chronic inflammation and IR, the hazard ratio (HR) and 95% confidence interval (CI) for stroke in the higher chronic inflammation group was 1.64 (1.31–2.07), the HR and 95%CI for the higher IR group was 1.51 (1.19–1.90), and for the group with both higher levels of chronic inflammation and IR it was 1.95 (1.58–2.41). In addition, IR mediated 15.6% of the effect of chronic inflammation on stroke; chronic inflammation mediated 13.1% of the effect of IR on stroke.</p> Conclusions <p>Chronic inflammation and IR have independent and superimposed effects on new-onset stroke risk and mediate each other. In primary care and public health services, the use of hsCRP and MetS-IR to assess the body's chronic inflammation and IR status and further assess its risk of a new stroke is a simple and effective new approach.</p>