Background: Spinal Cord Injury (SCI) is one of the leading causes of severe neurological deficits worldwide. The pathophysiology of SCI includes a primary injury followed by a cascade of secondary biochemical and cellular changes. Current pharmacological options are limited for significant recovery from SCI. The β-lactam antibiotic ceftriaxone (CEF) and N-acetylcysteine (NAC) have shown to induce neuroprotection in animal models of neurodegenerative disorders. Objectives: This study aimed to evaluate the effects of CEF, NAC, and their combination on the functional recovery and histological damage in experimental SCI. Methods: Rats were randomly divided into four groups (n = 7): Saline, CEF, NAC, and CEF + NAC. Then, SCI was performed on rats under general anesthesia using the Neurosciences Research Center (NSRC) impactor. Locomotor recovery following SCI was monitored using the locomotor rating scale of Basso, Beattie, and Bresnahan (BBB). At the end of the study, all rats were sacrificed, and spinal cord cross-sections were stained with hematoxylin and eosin for histopathological evaluation. Results: The CEF and NAC administration, either alone or in combination (CEF + NAC), significantly improved locomotor recovery following SCI in rats when compared to the saline group. The histological analysis showed that the severity of histopathological lesion in the spinal cord of rats was significantly lower in the CEF, NAC, and CEF + NAC groups than in the saline group. Conclusions: Treatment with CEF and NAC, either separately or in combination, promotes locomotor recovery following SCI, which is associated with the effective reduction of the histopathological lesion.