To determine the influence of smoking on blood and salivary superoxide dismutase enzyme levels among smokers, and to demonstrate the significant alterations in the levels of superoxide dismutase in association with patient age, periodontal disease status, smoking duration, and smoking frequency. This study also aimed to evaluate the use of saliva as a biological fluid for disease diagnosis. Ninety males aged 25–56 years were selected and included 30 smokers, 30 nonsmokers with chronic periodontitis, and 30 healthy controls. Clinical parameters such as the gingival index, pocket depth, and clinical attachment loss were recorded. Blood and saliva samples were collected and superoxide dismutase enzyme levels were analyzed using spectrophotometric assay. Superoxide dismutase enzyme levels in the blood and saliva were significantly higher in smokers than in nonsmokers and the controls (p < 0.05). A significant correlation existed between superoxide dismutase levels and clinical parameters. There was also a significant positive correlation between blood and salivary superoxide dismutase levels among the three groups. Systemic and local antioxidant status is affected by periodontal disease and by the impact of smoking. The increased blood and salivary superoxide dismutase enzyme levels in smokers may be an adaptive defense mechanism to counteract the increased reactive oxygen species production induced by smoking. This study emphasizes the importance of saliva as an easy noninvasive tool in diagnosing patients who are more prone to precancerous lesions and conditions, and its importance in patient education and motivation programs for smoking cessation.