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Aim The aim of the current study was to investigate that combination of the synbiotic supplementation in adjunct with non-surgical periodontal therapy (NSPT) is useful in treating periodontitis and biomarkers of oxidative stress in type 2 diabetes mellitus (T2DM) patients. Methods In this study, 47 patients suffering from DM and CP were recruited and randomly assigned to two groups. The intervention (n= 23) and control (n=24) groups received either multispecies probiotic supplement plus 100 mg fructo-oligosaccharide (500 mg in each capsule) or placebo capsule containing 500 mg wheat flour, respectively, every day for 8 weeks. All subjects were treated with NSPT during the intervention period. Serum levels of interleukin-1β (IL-1β), malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and periodontal indices including clinical attachment loss (CAL), pocket depth (PD) (main outcome), BOP, and plaque index were measured before and after the intervention. Results Supplementation with the synbiotic with NSPT led to a significant decrease in the levels of IL-1β, MDA, plaque index, PD, and CAL in the intervention group post-intervention (p < 0.05). The serum levels of TAC, SOD, and GPx were significantly increased in the intervention group compared with the baseline (p < 0.05). Consumption of synbiotic with NSPT, compared to the control, resulted in a significant decrease in the mean changes of IL-1β, MDA, and CAL (p < 0.05). Also, the mean changes of TAC and GPx were significantly higher in the intervention group compared with the control group (p < 0.05). Also, in the intervention group was seen a significant reduction in plaque index (p = 0.035) and BOP (p = 0.04) compared with the control group. Conclusion It was observed that synbiotic supplementation with NSPT may be beneficial in improving inflammatory, antioxidant, and periodontal status in T2DM patients with CP.