Tissue damage in spinal cord injury (SCI) occurs in two phases, with the primary damage being caused by the mechanical insult and the secondary damage mediated by a multifactorial cascade of events. Inflammation and hemorrhage from sheared blood vessels have been shown to significantly contribute to secondary damage after SCI. Blood breakdown products such as hemoglobin, heme and iron are pro-inflammatory and highly cytotoxic through lipid peroxidation, DNA oxidation and iron deposition. In the vasculature, breakdown products are sequestered by designated capture proteins. Haptoglobin (Hp) binds free hemoglobin and Hemopexin (Hx) binds and detoxifies heme, thereby preventing its toxic effects. However, low expression levels of Hp and Hx within the CNS limit the possibility of reducing tissue damage and enhancing functional recovery following SCI. Although a recent study showed that the absence of Hx impaired functional recovery and aggravated the lesion in murine model of SCI, mechanistic evidence of the role of Hx during secondary damage lacking. We investigated the role of Hx on injury progression and functional outcome in male and female mice following SCI. Our data indicate that Hx is expressed predominantly in astrocytes, while its receptor LRP is expressed by macrophages. Neither Hx nor LRP protein expression changed significantly over time after SCI In accordance with previous data, Hx^−/− mice showed reduced locomotor recovery compared to wildtype mice, with a more. While prominent effect in female mice. Interestingly, both male and female Hx^−/− mice showed an increase of axonal damage compared to wildtype mice. These results indicate that Hx may be protective following SCI and that boosting Hx availability could result in improved functional recovery and reduced secondary damage after SCI.