Epstein-Barr virus (EBV) infection is associated with B cell lymphomas in humans. The latent membrane protein 1 (LMP-1) of EBV constitutively activates the JAK/STAT signaling pathway and contributes to the proliferation of EBV-infected primary human B lymphocytes. Thus, targeting LMP1-induced JAK/STAT signaling may prove effective in treating B-cell lymphomas. The extract of the fruiting body of Antrodia cinnamomea, has been reported to have cytotoxicity on blood cancer cells. Here, we report that the bioactivity of antcin H, an analog of the JAK2 inhibitor zhankuic acid A (ZAA), inhibits LMP1-induced JAK/STAT related signaling and induces lymphoma cell line apoptosis. Moreover, antcin H enhances low-dose methotrexate (MTX) cytotoxicity against lymphoma cells. Treatment of antcin H with low-dose MTX significantly suppressed tumor growth and prolonged the survival of tumor-bearing mice. Our findings indicate antcin H as a potential therapeutic agent for the treatment of EBV-infected cancer cells.