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Many acute viral infections target tissue Mϕs, yet the mechanisms of Mϕ‐mediated control of viruses are poorly understood. Here, we report that CD40 expressed by peritoneal Mϕs restricts early infection of a broad range of RNA viruses. Loss of CD40 expression enhanced virus replication as early as 12–24 h of infection and, conversely, stimulation of CD40 signaling with an agonistic Ab blocked infection. With peritoneal cell populations infected with the filovirus, wild‐type (WT) Ebola virus (EBOV), or a BSL2 model virus, recombinant vesicular stomatitis virus encoding Ebola virus glycoprotein (rVSV/EBOV GP), we examined the mechanism conferring protection. Here, we demonstrate that restricted virus replication in Mϕs required CD154/CD40 interactions that stimulated IL‐12 production through TRAF6‐dependent signaling. In turn, IL‐12 production resulted in IFN‐γ production, which induced proinflammatory polarization of Mϕs, protecting the cells from infection. These CD40‐dependent events protected mice against virus challenge. CD40−/− mice were exquisitely sensitive to intraperitoneal challenge with a dose of rVSV/EBOV GP that was sublethal to CD40+/+ mice, exhibiting viremia within 12 h of infection and rapidly succumbing to infection. This study identifies a previously unappreciated role for Mϕ‐intrinsic CD40 signaling in controlling acute virus infection. [ABSTRACT FROM AUTHOR]