ABSTRACT Armed with two distinct targeting moieties, artificially created bispecific agents can uniquely modulate various processes and events implicated in human health and diseases. Despite recent approvals of multiple bispecific therapeutics, generation of homogeneous dual‐targeting constructs with desired pharmacological properties remains technically challenging. Here, we report a strategy for synthesis of bispecific agents by utilizing CD38, a member of the ADP‐ribosyl cyclase family, and its covalent inhibitor. A model ADP‐ribosyl cyclase‐enabled bispecific conjugate (ARC‐BsC) against human T‐cell CD3 and prostate‐specific membrane antigen (PSMA) is generated through site‐specific conjugation of an anti‐CD3 antibody‐CD38 fusion with the CD38 covalent inhibitor derivatized by a PSMA small‐molecule ligand. The resulting ARC‐BsC can redirect and activate cytotoxic T cells toward killing PSMA‐expressing tumor cells, eliciting highly potent and selective anti‐cancer immunity in vitro and in vivo. This proof‐of‐concept work demonstrates ARC‐BsC as a potentially general approach for the development of bispecific therapeutics with diverse applications.