Inflammation and excessive oxidative stress (OS) contribute to spinal cord injury (SCI) progression. Targeting inflammation and OS has emerged as a promising strategy for SCI treatment. Cepharanthine (CEP), derived from Stephania cepharantha, possesses notable anti-inflammatory and antioxidant properties, yet its effects on SCI have not been previously explored. In this study, we evaluated the therapeutic potential of CEP on motor recovery, inflammation, OS, and neuronal integrity in SCI rats. Basso-Beattie-Bresnahan (BBB) scores and inclined plane test results demonstrated that CEP treatment (10 mg/kg/day and 20 mg/kg/day, administered intraperitoneally) significantly improved locomotor function at various time points (7, 14, 21, and 28 days after injury) compared to SCI controls. Additionally, CEP treatment suppressed the activation of the NLRP3 inflammasome, as evidenced by reduced levels of NLRP3 and ASC, and decreased pro-inflammatory cytokines (IL-1 and IL-18) in the spinal cord. CEP also inhibited neuronal pyroptosis, as shown by reduced Casp-1 expression and lactase dehydrogenase (LDH) release. Furthermore, Nissl staining revealed that CEP treatment effectively prevented neuronal loss in the spinal cord tissues. CEP also ameliorated OS, with significant reductions in malondialdehyde (MDA) levels and enhanced activities of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Finally, CEP activated the Nrf2/HO-1 signaling pathway, which is known to play a key role in cellular defense against OS, and inhibited NF-B activation, a major mediator of inflammation. These findings suggest that CEP has therapeutic potential for promoting functional recovery and protecting against secondary damage in SCI, likely through its anti-inflammatory, antioxidative, and neuroprotective effects.