Macrophages persist indefinitely at sites of spinal cord injury (SCI) and contribute to both pathological and reparative processes. While the alternative, anti-inflammatory (M2) phenotype is believed to promote cell protection, regeneration, and plasticity, pro-inflammatory (M1) macrophages persist after SCI and contribute to protracted cell and tissue loss. Thus, identifying non-invasive, clinically viable, pharmacological therapies for altering macrophage phenotype is a challenging, yet promising, approach for treating SCI. Azithromycin (AZM), a commonly used macrolide antibiotic, drives anti-inflammatory macrophage activation in rodent models of inflammation and in humans with cystic fibrosis. We hypothesized that AZM treatment can alter the macrophage response to SCI and reduce progressive tissue pathology. To test this hypothesis, mice (C57BL/6J, 3-month-old) received daily doses of AZM (160 mg/kg) or vehicle treatment via oral gavage for 3 days prior and up to 7 days after a moderate-severe thoracic contusion SCI (75-kdyn force injury). Fluorescent-activated cell sorting was used in combination with real-time PCR (rtPCR) to evaluate the disposition and activation status of microglia, monocytes, and neutrophils, as well as macrophage phenotype in response to AZM treatment. An open-field locomotor rating scale (Basso Mouse Scale) and gridwalk task were used to determine the effects of AZM treatment on SCI recovery. Bone marrow-derived macrophages (BMDMs) were used to determine the effect of AZM treatment on macrophage phenotype in vitro. In accordance with our hypothesis, SCI mice exhibited significantly increased anti-inflammatory and decreased pro-inflammatory macrophage activation in response to AZM treatment. In addition, AZM treatment led to improved tissue sparing and recovery of gross and coordinated locomotor function. Furthermore, AZM treatment altered macrophage phenotype in vitro and lowered the neurotoxic potential of pro-inflammatory, M1 macrophages. Taken together, these data suggest that pharmacologically intervening with AZM can alter SCI macrophage polarization toward a beneficial phenotype that, in turn, may potentially limit secondary injury processes. Given that pro-inflammatory macrophage activation is a hallmark of many neurological pathologies and that AZM is non-invasive and clinically viable, these data highlight a novel approach for treating SCI and other maladaptive neuroinflammatory conditions.