Autoimmune disorders are intricate conditions where the immune system directs its attack towards the body's tissues. The goal is to perform a thorough meta-analysis focusing on the genetic and epigenetic aspects of autoimmune disorders, specifically examining the role of the PTPN22 gene, particularly the rs2476601 variation, in influencing susceptibility to autoimmune diseases. The study followed PRISMA 2020 guidelines and PROSPERO registration and conducted a comprehensive meta-analysis to explore the association between PTPN22 gene variations and autoimmune disorders. Case-control studies presenting genotype information were included, and quantitative data analysis was performed using MetaGenyo software. The meta-analysis included 43 studies with 20,669 controls and 9,397 cases of autoimmune diseases, focusing on the PTPN22 gene rs2476601 polymorphism. Significant associations were observed between the PTPN22 polymorphisms across multiple genetic models, including allelic, dominant, and recessive models. However, no link was found between the over-dominant model. The obtained p-values were < 0.01 for the allele model (C vs T; OR: 0.63, 95% CI: 0.48-0.81, I = 92%), 0.03 for the dominant model (CC + CT vs. TT; OR: 0.47, 95% CI: 0.24-0.95, I = 87%), and < 0.01 for the recessive model (TT vs. CT + CC; OR: 0.61, 95% CI: 0.47-0.79, I = 89%). However, the over-dominant model (CT vs. CC + TT; OR: 1.68, 95% CI: 1.32-2.15, I = 86%) did not show a significant p-value (> 0.05). This meta-analysis emphasizes the significant impact of PTPN22 gene variations on autoimmune diseases, suggesting its potential as a biomarker for assessing risk and guiding targeted interventions.