Peptidylarginine deiminases 2 (PADI2) is an enzyme that catalyzes the conversion of arginine residues to citrulline on protein peptides. Aberrant activation of PADI2 can induce excessive tissue inflammation and immune responses, thereby exacerbating the progression of autoimmune diseases (ADs). Through citrullination, PADI2 modifies protein structure and immunogenicity, influencing the production of autoantibodies and regulating the activity of immune cells such as neutrophils and macrophages. This review provides an overview of PADI2’s functions and its pivotal role in ADs, with the Objective of elucidating the mechanisms underlying ADs pathogenesis and identifying novel therapeutic targets and strategies for related diseases.