Objectives: To investigate the association between shift work patterns and insulin resistance (IR) surrogates, and the potential moderating role of physical activity (PA). Material and Methods: This cross-sectional study analysed 992 adults from National Health and Nutrition Examination Survey (NHANES) 2017–2018. Participants were categorized into daytime and variable shift workers. Four IR surrogates were evaluated. Weighted linear regression models adjusted for demographics, anthropometrics, lifestyle, and clinical covariates assessed associations between work schedules, PA, and metabolic outcomes. Sensitivity analyses excluded individuals with diabetes. Results: Compared to daytime workers, variable shift workers had significantly higher triglycerides, lower high-density lipoprotein-cholesterol (HDL-C), and elevated levels of all IR surrogates. Physical activity was inversely associated with triglyceride-glucose – waist circumference (TyG-WC) and body mass index (TyG-BMI). The most pronounced combined beneficial association was observed for daytime schedules combined with sufficient PA on homeostasis model assessment of IR (HOMA‑IR) and TyG-BMI. However, when stratified, work-related PA correlated positively with these indices, while leisure-time PA exhibited stronger inverse associations; transportation PA showed no association. Conclusions: Variable shift work and insufficient PA are associated with adverse metabolic profiles and elevated IR. As a modifiable factor, PA may help mitigate metabolic risk in shift-working populations. Int J Occup Med Environ Health. 2026;39(5)