Non-Hodgkin lymphoma (NHL) is a genetically heterogeneous disease with several oncogenic events implicated in the transformation of normal developing B lymphocytes. The objective of this study was to elucidate the signal transduction-based antitumor mechanism(s) of action for the anti-CD40 monoclonal antibody dacetuzumab (SGN-40) in NHL. We report that dacetuzumab activates two distinct proapoptotic signaling pathways, overcoming transformation events key to the pathogenesis of NHL. Dacetuzumab-mediated CD40 signaling constitutively activated the nuclear factor-κB and mitogen-activated protein kinase signaling pathways producing the sustained downregulation of B-cell lymphoma 6 (BCL-6), an oncoprotein implicated in lymphomagenesis. Loss of BCL-6 resulted in c-Myc downregulation and activation of a transcriptional program characteristic of early B-cell maturation, concomitant with reduced proliferation and cell death. In a second mechanism, dacetuzumab signaling induced the expression of the proapoptotic p53 family member TAp63α and downstream proteins associated with the intrinsic and extrinsic apoptotic machinery. Dacetuzumab was synergistic in combination with DNA-damaging chemotherapeutic drugs, correlating with TAp63α upregulation. Furthermore, dacetuzumab augmented the activity of rituximab in combination with multiple chemotherapies in the xenograft models of NHL. The ability of dacetuzumab signaling to circumvent oncogenic events and potentiate the activity of chemotherapy regimens provides a unique therapeutic approach to NHL.