Metabolic syndrome (MetS) is a cluster of metabolic disorders associated with an increased risk of cardiovascular disease and type 2 diabetes. The aim of this study was to investigate the interaction between physical activity and smoking on the development of MetS and its components. In this repeated cross-sectional study, data from the Iranian STEPwise non-communicable disease risk factor surveillance (STEPS) surveys (2007, 2011, and 2016) were analyzed, which included 40,046 participants aged 25-64 years. Physical activity was categorized as low, moderate, or vigorous based on metabolic equivalents (MET) minutes per week. Smoking status was defined based on self-reported information as either a current smoker or a non-smoker. MetS was diagnosed using established criteria. Interactive association was analyzed using relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI), and weighted logistic regression. The weighted prevalence of MetS was higher in the low physical activity group (34.32%) than in the current smokers group (26.63%). Positive interactions between low physical activity and smoking were observed for MetS (RERI = 0.23, AP = 0.25, SI = 0.23), abdominal obesity (RERI = 0.24, AP = 0.31, SI = 0.47) and high triglycerides (RERI = 0.19, AP = 0.19, SI = 0.12). Moderate/vigorous physical activity combined with smoking was associated with lower odds of abdominal obesity, hypertension and elevated fasting blood glucose, but higher odds of low HDL cholesterol. A physical inactivity appears to be a greater potential risk factor for MetS than smoking. The interaction between low physical activity and smoking exacerbates the odds of MetS and several of its components. Promoting physical activity and smoking cessation should be prioritized in MetS prevention and treatment strategies.