Macrophages are ubiquitous innate immune cells that play a central role in health and disease by functionally “polarizing” to distinct phenotypes, which are broadly divided into classical inflammatory responses (M1) and alternative responses (M2) that promote immune suppression and wound healing. Although macrophages are attractive therapeutic targets, incomplete understanding of polarization limits clinical manipulation. While individual stimuli, pathways, and genes involved in polarization have been identified, how macrophages evaluate complex in vivo milieus comprising multiple divergent stimuli remains poorly understood. Here, we used combinations of “incoherent” stimuli – those that individually promote distinct macrophage phenotypes – to elucidate how the immunosuppressive, IL-10-driven macrophage phenotype is induced, maintained, and modulated under such combinatorial stimuli. The IL-10-induced immunosuppressive phenotype was largely dominant but required sustained IL-10 signaling to maintain this phenotype. Our data also implicate the intracellular protein, BCL3, as a key mediator of the IL-10-driven phenotype. IL-12 did not directly impact polarization of IL-10-treated macrophages, but IFNγ disrupted a positive feedback loop that may reinforce the IL-10-driven phenotype in vivo. This novel combinatorial perturbation approach thus generated new insights into macrophage decision making and local immune network function.