Efficacious antitumor immune responses must overcome multiple suppressive mechanisms in the tumor microenvironment (TME) to control cancer progression. In this study, we demonstrate that dual targeting of suppressive myeloid populations by inhibiting CSF-1/CSF-1R signaling and activation of antigen presenting cells (APCs) with agonist anti-CD40 treatment confers superior antitumor efficacy and increased survival compared to monotherapy treatment in preclinical tumor models. Concurrent CSF-1R blockade and CD40 agonism lead to profound changes in the composition of immune infiltrates, causing an overall decrease in immunosuppressive cells and a shift toward a more inflammatory milieu. Anti-CD40/anti-CSF-1R treated tumors contain decreased tumor-associated macrophages (TAMs) and Foxp3+ regulatory T cells. This combination approach increases maturation and differentiation of pro-inflammatory macrophages and dendritic cells and also drives potent priming of effector T cells in draining lymph nodes. As a result, tumor-infiltrating effector T cells exhibit improved responses to tumor antigen rechallenge. These studies show that combining therapeutic approaches may simultaneously remove inhibitory immune populations and sustain endogenous antitumor immune responses to successfully impair cancer progression.