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Background Interleukins are the markers of inflammation and the lipid profile reveals the likelihood of arising cardiovascular disease (CVD). The present study aimed to assess and correlate the influence of non‐surgical periodontal therapy (NSPT) on serum lipid profile and Interleukin‐6 (IL‐6) and Interleukin‐8 (IL‐8) in patients with Stage III periodontitis. Methods Sixty patients with the age range of 35–60 years with Stage III periodontitis were included by evaluating for periodontal parameters such as Probing pocket depth (PPD) and clinical attachment levels (CAL). NSPT was performed at baseline, 3 and 6 months. Biochemical parameters like serum lipid parameters of total cholesterol (TC), triglycerides (TG), low‐density lipopolysaccharide (LDL), high‐density lipopolysaccharide (HDL), and IL‐6 and IL‐8 serum levels were assessed at baseline and 6 months' post‐NSPT. Results The results indicated a significant reduction (p < 0.0001) in the PPD (2.75 ± 0.41), CAL (3.23 ± 0.56), lipid profile, and serum cytokine levels 6 months' post‐NSPT as compared to baseline. A highly significant (p < 0.0001) percentage reduction was observed in the IL‐6 (35.3%), IL‐8 (41.6%), TC (7.5%), TG (1.78%), LDL (6.2%), and HDL (−21.8%) clinical and biochemical parameters at 6 months' recall post‐NSPT. Conclusion Non‐surgical periodontal therapy caused a significant reduction in the levels of serum pro‐inflammatory cytokines IL‐6 and IL‐8 as well as the lipid biomarkers TC, TG, LDL, and increase values of HDL. These findings imply a considerable reduction in the risk of developing CVD in patients with Stage III periodontitis.