The aim of this article was to determine the effect of nonsurgical periodontal therapy on clinical parameters and also to evaluate serum level of interleukin (IL)-6 and tumor necrosis factor (TNF)-α in chronic periodontitis patients with and without hypothyroidism. Subjects were 40 female patients (20 systemically healthy subjects with chronic periodontitis and 20 subjects with hypothyroidism and chronic periodontitis). Clinical parameters like plaque score, gingival score, gingival recession, probing pocket depth, and clinical attachment level were recorded at baseline and 4 weeks after nonsurgical periodontal therapy. Nonsurgical periodontal therapy included oral hygiene instructions and full-mouth scaling and root planing. A total of 5 mL of venous blood sample was collected from each subject at baseline and 4 weeks after nonsurgical periodontal therapy. The clinical parameters and biochemical parameters like IL-6 and TNF-α in both groups showed pronounced reduction at the end of 4 weeks following nonsurgical periodontal therapy. However, simultaneous comparison of clinical and biochemical parameters between the two groups was not statistically significant. This study provides evidence that nonsurgical periodontal therapy contributes to reduction in serum level of IL-6 and TNF-α in systemically healthy subjects with chronic periodontitis and subjects with hypothyroidism and chronic periodontitis. The prevalence of periodontitis as well as hypothyroidism is increasing nowadays. Interleukin-6 and TNF-α are found to play a significant role in pathobiology of both periodontitis and hypothyroidism. With the treatment of periodontitis, it is found that there is improvement in periodontal and thyroid status of the patients. So, it is an alert to health professionals about the relation of hypothyroidism and periodontitis so that they consider a multidisciplinary approach.