Lymphoma is a potentially life threatening disease. The goal of this study was to investigate the therapeutic potential of a natural triterpenoid, Ganoderic acid A (GA‐A) in controlling lymphoma growth both in vitro and in vivo. Here, we show that GA‐A treatment induces caspase‐dependent apoptotic cell death characterized by a dose‐dependent increase in active caspases 9 and 3, up‐regulation of pro‐apoptotic BIM and BAX proteins, and a subsequent loss of mitochondrial membrane potential with release of cytochrome c. In addition to GA‐A's anti‐growth activity, we show that lower doses of GA‐A enhance HLA class II‐mediated antigen (Ag) presentation and CD4+ T cell recognition of lymphoma cells in vitro. The therapeutic relevance of GA‐A treatment was also tested in vivo using the EL4 syngeneic mouse model of metastatic lymphoma. GA‐A‐treatment significantly prolonged survival of EL4 challenged mice and decreased tumor metastasis to the liver, an outcome accompanied by a marked down‐regulation of STAT3 phosphorylation, reduction myeloid‐derived suppressor cells (MDSCs), and enhancement of cytotoxic CD8+ T cells in the host. Thus, GA‐A not only selectively induces apoptosis in lymphoma cells, but also enhances cell‐mediated immune responses by attenuating MDSCs, and elevating Ag presentation and T cell recognition. The demonstrated therapeutic benefit indicates that GA‐A is a candidate for future drug design for the treatment of lymphoma. J. Cell. Biochem. 116: 102–114, 2015. © 2014 Wiley Periodicals, Inc.