Epstein-Barr virus (EBV) is ubiquitous in humans, which infects more than 90% of adults globally. Beyond its established association with malignancies, EBV infection is linked to several autoimmune diseases including systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis and Sjögren syndrome. SLE is characterized by systemic inflammation and multiorgan damage with unpredictable relapsing-remitting clinical course. Although significant evidence supports EBV infection as a contributing factor in SLE pathogenesis, the exact mechanisms linking EBV to SLE onset remain to be fully elucidated. Molecular mimicry is among the potential factors that may drive SLE development. Importantly, given this association, development of therapies targeting EBV is promising for novel SLE treatment.