OBJECTIVES: In this study, we aimed to clarify the relationship between physical activity (PA) and diabetes mellitus (DM), as well as the mediating role of Systemic Immune-Inflammatory Index (SII) in the relationship. DESIGN: A cross-sectional study. SETTING: National Health and Nutrition Examination Survey (NHANES) data collection took place in the USA at participants' homes and mobile examination centres with specialised equipment. PARTICIPANTS: The study population consisted of 9493 American adults aged 20 and above from the NHANES 2005 to 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: Information on the specific PA was reported through self-administered questionnaire by participants and we used this information to calculate a metabolic equivalent score for the particular PA. The calculation of SII follows a standard formula: SII=P (platelets)×N (neutrophils)/L (lymphocytes). RESULTS: A total of 9493 participants were included, with 1672 diagnosed with DM. The participants with DM were more inclined to have lower levels of PA while having higher levels of SII. In all three models, high levels of PA were significantly negatively associated with the risk of DM compared with moderate levels of PA, and a non-linear association between natural logarithm-physical activity (Ln-PA) and DM was observed. Furthermore, there was a significant reduction in DM risk for Ln-PA >
6.71 in all models. Mediation analysis showed that SII mediated the relationship between PA and DM, as well as between Ln-PA and DM, with respective mediation proportions of 4.32% and 12.141%, as well as 3.12% and 10.46% after adjusting for covariates. CONCLUSION: This study investigated the relationship among PA, SII and DM. We provide robust evidence supporting the inverse association between PA and DM risk while highlighting the mediating role of inflammation, as reflected by SII. These findings contribute valuable insights to inform public health strategies and clinical interventions aimed at reducing the global burden of DM.