Background <p>Overactive bladder (OAB) is an intricate disorder with an unclear pathophysiological relationship with inflammation. This study employs the Systemic Inflammation Response Index (SIRI) as a quantitative measure of systemic inflammatory status and explores its association with both the risk and severity of OAB, as assessed by the Overactive Bladder Symptom Score (OABSS).</p> Methods <p>Population data from the National Health and Nutrition Examination Survey (NHANES) in 2005–2020 were extracted. Weighted logistic regression and weighted linear regression models were utilized to examine the relation of SIRI to OAB risk and OABSS. The possible nonlinear relation of SIRI to clinical outcomes was examined via restricted cubic spline (RCS) models. In addition, subgroup analyses and interaction tests helped to explore the consistency of these associations across subpopulations.</p> Results <p>23,915 individuals were encompassed for our analysis. 9011 (21%) were diagnosed with OAB. Both weighted linear and logistic regression analyses demonstrated a significant link of SIRI to OAB risk and symptom severity (fully adjusted model: <i>β</i> = 0.143, 95% CI 0.086–0.200, <i>P</i> &lt; 0.001; OR = 1.268, 95% CI 1.122–1.413, <i>P</i> &lt; 0.001). The RCS model showed a significant nonlinear relation of SIRI to clinical outcomes. Subgroup analyses further demonstrated the consistency of these associations across various subgroups.</p> Conclusions <p>SIRI is a significant risk factor for OAB, and higher SIRI levels are strongly related to heightened OAB symptom severity.</p>