Objectives <p>The association between interleukin-10 (IL-10) and protein tyrosine phosphatase non-receptor type 22 (PTPN22) has been implicated in immune regulation and autoimmune risk. This meta-analysis aimed to evaluate the association between specific gene variants rs1800896, rs1800871, and rs1800872 in interleukin-10 and rs2476601 in protein tyrosine phosphatase non-receptor type 22 (PTPN22) with rheumatoid arthritis susceptibility.</p> Methods <p>The studies included in this article were obtained by using online databases. We searched databases such as Scopus, PubMed, Embase, and Web of Science for case–control articles related to focusing on studies published from 2019 to 2025.</p> Results <p>A total of fifteen case–control studies were included. The rs1800896 variant in interleukin-10 was significantly associated with increased rheumatoid arthritis risk under the allele contrast model (G vs. A: OR 1.15, 95% CI 1.01 to 1.32, <i>p</i> = 0.03) and the dominant model (GG + GA vs. AA: OR 1.28, 95% CI 1.06 to 1.54, <i>p</i> = 0.01). No significant associations were found for rs1800871 or rs1800872 under any genetic model. For the PTPN22 gene, the rs2476601 variant was significantly protective under the dominant model (CC + CT vs. TT: OR 0.39, 95% CI 0.21 to 0.72, <i>p</i> = 0.002). Subgroup analyses were feasible for IL-10 (rs1800896, rs1800871, rs1800872) and PTPN22 (rs2476601), but no significant associations were identified, and power analysis confirmed the robustness of our results.</p> Conclusions <p>This meta-analysis identified a significant association between the interleukin-10 rs1800896 variant and increased risk of rheumatoid arthritis, and a protective role for the rs2476601 variant in PTPN22. Variants rs1800871 and rs1800872 did not show any association. These findings emphasize the importance of genetic screening in understanding disease susceptibility and the need for further studies across diverse populations to refine the genetic risk profile of rheumatoid arthritis.</p>