Rheumatoid arthritis (RA) is a multifaceted autoimmune disorder defined by persistent inflammation and joint damage. This study explores the intricate relationship between RA severity and interleukin-38 (IL-38), a cytokine having anti-inflammatory properties. Our research reveals a strong connection between elevated plasma IL-38 levels and the severity of RA, indicating IL-38’s crucial role in modulating inflammation. Elevated ESR levels in RA patients highlight active inflammation. Genetic analysis shows specific IL-38 polymorphisms associated with RA susceptibility, emphasizing the disease’s genetic basis. These findings position IL-38 as a promising indicator for assessing rheumatoid arthritis RA severity by providing valuable insights into its genetic mechanisms. Understanding IL-38-related pathways could revolutionize RA management strategies.