Enhancing granuloma development and effector function, but without inducing the pathology associated with excess granulomatous inflammation, poses a major challenge for immunotherapeutic intervention against diseases such as visceral leishmaniasis (VL). Here, we demonstrate that a chimeric fusion protein (OX40L‐Fc) which stimulates T cells through OX40 and a monoclonal antibody which blocks CTLA‐4, an inhibitory receptor on T cells, both enhanced the rate of granuloma maturation, CD4⁺ T cell proliferation, and killing of Leishmania. Costimulation‐based therapy induced no adverse fibrotic or necrotic reactions, and had no significant effect on the levels of endogenous anti‐inflammatory cytokines (IL‐10 and TGF‐β). Furthermore, both OX40L‐Fc and anti‐CTLA4could be co‐administered with conventional anti‐leishmanial drugs. Until now, enhancing T cell immunity by the manipulation of costimulatory pathways has only received serious attention for cancer immunotherapy, but our data provide a compelling argument for the evaluation of this approach in human VL and other infectious diseases.