Dystrophic muscle is characterized by chronic injury and a steady recruitment of inflammatory Ly6C ^hi monocytes. Recent studies have identified the spleen as the dominant reservoir of these cells during chronic inflammation. Here, we investigated the contribution of splenic Ly6C ^hi monocytes to dystrophic muscle pathology. Using the mdx mouse model of muscular dystrophy, we show that Ly6C ^hi monocytes accumulate in great numbers in the spleen over the course of the disease. The chemokine receptor CCR2 was upregulated on Ly6C ^hi monocytes in mdx spleen before disease onset, thereby enabling their recruitment to dystrophic muscle. Splenectomy performed before disease onset significantly reduced the number of Ly6C ^hi monocytes infiltrating dystrophic limb muscle. Moreover, in the absence of splenic Ly6C ^hi monocytes there was a significant reduction in dystrophic muscle inflammation and necrosis, along with improved regeneration during early disease. However, during late disease, a lack of splenic Ly6C ^hi monocytes adversely affected muscle fiber repair, due to a delay in the phenotypic shift of proinflammatory F4/80 ⁺ Ly6C ^hi CD206 ^lo to antiinflammatory F4/80 ⁺ Ly6C ^lo CD206 ⁺ macrophages. Overall, we show that the spleen is an indispensable source of Ly6C ^hi monocytes in muscular dystrophy and that splenic monocytes are critical players in both muscle fiber injury and repair.