The interaction between CD200 and its receptor CD200R1 plays a key role in modulating immune responses in nervous system disorders. This study explored the function of CD200R1 in local and systemic inflammation following spinal cord injury (SCI) using CD200R1-knockout (CD200R1-/-) mice. Following a low thoracic contusion injury, CD200R1-/- mice exhibited increased macrophage infiltration at the injury site, with a greater proportion of pro-inflammatory Ly6C + macrophages. Myelin phagocytosis was impaired in CD200R1-/- macrophages both ex vivo and in vitro, indicating a reduced capacity to clear myelin debris. Despite these immune alterations, CD200R1 deficiency did not affect spontaneous locomotor recovery post-SCI, as measured by the Basso Mouse Scale. However, CD200R1-/- mice tended to lose more weight after injury, suggesting systemic effects. In uninjured (naïve) conditions, CD200R1-/- mice showed reduced spleen weight and lymphocyte counts, along with lower mRNA expression of inflammatory cytokines TNFα, IL6, and CCL2, though no significant differences were seen in splenic immune cell populations. Altogether, these results suggest that CD200R1 is an important factor regulating myelin phagocytosis by macrophages and maintaining normal immune and splenic homeostasis under both injured and naïve conditions.