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Disturbances in extracellular and intracellular homeostasis alter cell volume, but the consequences for macrophage inflammatory responses are poorly understood. We demonstrate that macrophages use cell volume control as a danger-sensing mechanism to promote and augment inflammation. Using volume-regulated anion channel (VRAC)\u2013deficient macrophages, which lack cell volume control under hypo-osmotic conditions, we show that cell volume disruptions drive transcriptomic reprogramming and induction of inflammation. Cell volume disruption induced type I interferon signaling through a DNA- and TBK1-dependent mechanism, but independent of cGAS and 2\u20323\u2032-cGAMP transport. VRAC deficiency enhanced macrophage antiviral responses to influenza infection. Cell volume changes synergized with diverse pathogen-associated molecular pattern\u2013mediated signaling to augment type I interferon responses and exacerbate the cytokine storm in mouse models of hyperinflammation. 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