Deranged antioxidant status may play a role in the extreme tissue breakdown in periodontitis. Apart from periodontitis, smoking also plays a major contributing role in increasing oxidative stress of periodontal tissues. Hence this study aimed to evaluate & compare the salivary Glutathione Reductase (GR) levels following non-surgical periodontal therapy (NSPT) in smokers and non-smokers with and without periodontitis. A total of 76 subjects were divided into four groups smokers with Periodontitis (n = 19), smokers without Periodontitis (n = 19), non-smokers with periodontitis (n = 19), and non-smokers without periodontitis (n = 19). Clinical parameters such as plaque index (PI), gingival index (GI) probing pocket depth (PPD), and clinical attachment level (CAL) were assessed at baseline, on the 14th day, and at 1 month. Salivary GR levels were analyzed by ELISA pre and post-NSPT. NSPT was associated with improvement in PI and GI scores. Significant reduction in PPD and gain in CAL were observed post-NSPT (p<0.001). On intra-group comparison, there was a significant increase in GR activities from baseline to 1 month in each study group after NSPT (p<0.001). On intergroup comparison, there was no significant difference in GR activities among the study groups (0<0.188). Based on the findings of this study it can be concluded that improved oral hygiene and NSPT were effective in increasing salivary GR levels and reducing oxidative stress. Hence salivary GR levels could be considered a prognostic indicator in the assessment of periodontal status among smokers and periodontitis subjects.