Ebola virus (EBOV) causes severe systemic disease in humans characterized by high virus replication and dysregulated innate and adaptive immunity. EBOV infection is recognized by the RIG-I-like receptors (RLR) that signal through the adapter molecule, mitochondrial antiviral signaling protein (MAVS) to induce expression of IFN-I. Wild-type EBOV (WT-EBOV) is not lethal in immunocompetent mice, although adaptation to mice is associated with mutations that increase virus replication and virulence. In the mouse model, IFN-I is required for resistance to WT-EBOV, but little is known regarding the innate signaling pathways that coordinate this response in vivo. To explore how MAVS orchestrates cellular responses to EBOV, we infected MAVS knockout mice (MAVS-/-) with WT- or mouse adapted (MA)- EBOV. MAVS deficiency rendered mice highly susceptible to lethal disease following infection with MA-EBOV, and increased morbidity during infection with WT-EBOV compared to control mice. MAVS-/- mice had increased viral titers, reduced circulating IFN-I and a global transcriptional profile indicating reduced RLR signaling, increased inflammatory gene expression and increased cell death in the liver. Immune cell dynamics predicted by digital cell quantification suggested that macrophages and dendritic cells have significant roles in MAVS-dependent responses to EBOV. To confirm these findings, we conditionally deleted MAVS from monocyte/macrophage populations (LysM-Cre+MAVSfl/fl) or dendritic cells (CD11c+Cre MAVSfl/fl) while leaving MAVS expression in other cell types intact. LysM-Cre+MAVSfl/fl and CD11c+Cre MAVSfl/fl mice were uniformly susceptible to lethal disease similar to MAVS-/- mice. Surprisingly, the role of macrophages was not due to intrinsic control of virus replication or IFN production. In conclusion, MAVS signaling in either monocytes/macrophages or myeloid-lineage DCs dominantly determines disease severity and outcome. Our data suggests the role of MAVS-dependent macrophage responses is likely indirect and may coordinate critical cellular innate and adaptive responses that ultimately control infection.