Traumatic spinal cord injury (SCI) has devastating physical, psychosocial, and vocational implications for patients and caregivers. Heterophyllin B (HB) is a brain-permeable cyclopeptide from Pseudostellaria heterophylla that promotes axonal regeneration and neuroinflammation. However, the efficacy of HB in improving functional recovery following SCI and the underlying mechanisms remain unclear. This study utilized a murine model for SCI assessment to evaluate the therapeutic effects of HB. following HB intervention, functional recovery post-SCI, was assessed through the Basso Mouse Scale, gait analysis, and the detection of motor-evoked potentials (MEPs). RNA sequencing was used to study the roles of pyroptosis, oxidative stress, and autophagy in HB's impact on SCI. Techniques such as Western blot, immunofluorescence, and enzyme-linked immunosorbent assay were used to evaluate pyroptosis, oxidative stress, and autophagy markers. Associated virus vectors were used to suppress transcription factor EB (TFEB), an autophagy regulator, in a living organism. HB promoted autophagy by enhancing TFEB nuclear translocation. In contrast, it inhibited pyroptosis and oxidative stress. Based on using the adenosine monophosphate-activated protein kinase (AMPK) inhibitor Compound C, the AMPK-TRPML1-calcineurin pathway was involved in HB's regulation of TFEB. In summary, this study demonstrated that HB facilitated functional recuperation by stimulating TFEB-driven autophagy while simultaneously suppressing pyroptosis and oxidative stress after SCI, indicating its potential for clinical application.