2’-5’ oligoadenylate synthetase-like (OASL) is an interferon-stimulated gene (ISG) induced by type I interferons and a member of the OAS family. Unlike other family members, OASL lacks enzymatic activity but has diverse roles in antiviral defense and disease regulation. In mice, two orthologs, mOasl1 and mOasl2, share approximately 74% and 49% amino acid sequence homology with the human protein, respectively. Type I interferons, known for their antiviral functions, are also implicated in chronic inflammation and cancer, implying broader physiological roles for OASL. Both hOASL and mOasl2 restrict RNA virus replication through activation of retinoic acid-inducible gene I (RIG-I), while suppressing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling to promote DNA virus persistence. In addition, hOASL and mOasl1 regulate necroptosis through liquid-liquid phase separation-mediated recruitment of receptor-interacting serine/ threonine-protein kinase 3 (RIPK3) and Z-DNA-binding protein 1 (ZBP1). Beyond viral infection, OASL acts as a regulatory molecule in autoimmune and inflammatory disorders such as atherosclerosis, ischemia/reperfusion-induced liver injury, and virus-induced asthma. In cancer, hOASL promotes tumor progression by reprogramming lipid metabolism and enhances invasion in pancreatic and gastric adenocarcinomas. Collectively, these findings demonstrate that OASL functions as a central mediator linking antiviral and non-viral pathological processes. Its pleiotropic activities highlight its potential as a diagnostic and prognostic biomarker in infection- and inflammation-associated diseases.