Background <p>TNF-α inhibitors (anti-TNF-α) decrease the amount of inflammatory cells, osteoclast formation, and bone loss. The purpose of this study was to investigate the effect of non-surgical periodontal therapy (NSPT) combined with anti-TNF-α on oxidative stress in individuals with RA and periodontitis.</p> Methods <p>A total of 42 patients with RA and periodontitis who were treated with anti-TNF-α (<i>n</i> = 21) and not treated with anti-TNF-α (<i>n</i> = 21) were included in the study. Plaque index (PI), bleeding on probing (BOP), gingival index (GI), clinical attachment loss (CAL), and probing pocket depth (PPD) measurements were measured at baseline, at 3 months, and at 6 months after NSPT, and serum and gingival crevicular fluid (GCF) samples were obtained from the patients. RANKL/OPG, MMP-8, MDA, GSH, and OSI levels were evaluated using ELISA.</p> Results <p>In both groups, baseline PI, BOP, GI, PPD, and CAL decreased significantly after NSPT (<i>p</i> &lt; 0.05). The GCF RANKL/OPG ratio was statistically significantly lower in anti-TNF-α treated patients at baseline and at 6 months post-NSPT (<i>p</i> &lt; 0.05), and the serum OSI was significantly higher in anti-TNF-α treated patients at baseline (<i>p</i> &lt; 0.05). GCF MMP-8 increased significantly after NSPT in both groups compared with baseline (<i>p</i> &lt; 0.05). In those treated with anti-TNF-α, OSI and MDA decreased significantly after NSPT (<i>p</i> &lt; 0.05).</p> Conclusions <p>The data from this study suggest that anti-TNF-α therapy can suppress inflammation and alveolar bone resorption by affecting the RANKL/OPG ratio, MMP-8, and oxidative stress parameters, and thus increase the effectiveness of NSPT.</p> Trial registration <p>This study was retrospectively registered on ClinicalTrials.gov (NCT06818045), 2025-02-02.</p>