〔Abstract〕 Objective To investigate the ameliorative effect of vitamin D on sciatic nerve chronic compression injury (CCI) rats and its regulatory effect on nuclear factor κB (NF-κB)/cystathione-β-synthase (CBS)-hydrogen sulfide (H 2S) system. Methods Fifty rats were randomly divided into five groups: control group, model group, Vitamin D group, activator group, and activator + vitamin D group, with 10 rats in each group. Except for the control group, the rats in the other groups underwent sciatic nerve ligation to establish the CCI model. The vitamin D group received intraperitoneal injection of 500 mg/kg Vitamin D, the activator group received intraperitoneal injection of 10 mg/kg NF-κB activator lipopolysaccharide, and the activator + vitamin D group received intraperitoneal injection of 500 mg/kg vitamin D along with 10 mg/kg lipopolysaccharide. The control and model groups received intraperitoneal injection of an equal volume of saline, once per day for 2 weeks. The following parameters were compared among the groups: paw withdraw thermal latency (PWTL), mechanical withdrawal threshold (MWT), serum 25-hydroxyvitamin D 3 [25(OH)D 3] levels, H2S content, calcitonin gene-related peptide (CGRP), prostaglandin E2 (PGE2) levels, and the expression of vitamin D receptor (VDR), NF-κBp65, and CBS proteins in the L4-L6 dorsal root ganglia of rats. Results Compared with the control group, the model group showed decreased PWTL, MWT, 25(OH)D 3 levels and VDR protein expression, while H 2S content, CGRP and PGE2 levels, and NF-κBp65 and CBS protein expression significantly increased ( P<0.05). Compared with the model group, the vitamin D group exhibited increased PWTL, MWT, 25(OH)D 3 levels and VDR protein expression ( P<0.05), while H 2S content, CGRP and PGE2 levels, and NF-κBp65 and CBS protein expression significantly decreased ( P<0.05). Compared with the activator group, the activator + Vitamin D group showed increased PWTL, MWT, 25(OH)D 3 levels and VDR protein expression, and decreased H 2S content, CGRP and PGE2 levels and decreased NF-κBp65, CBS protein expression ( P<0.05). Compared with the vitamin D group, the activator + vitamin D group showed decreased PWTL, MWT, 25(OH)D 3 levels and VDR protein expression, while H 2S content, CGRP and PGE2 levels, and NF-κBp65 and CBS protein expression significantly increased ( P<0.05). ConclusionExogenous supplementation of vitamin D can relieve nerve pain and reduce pain sensitivity in CCI rats, possibly by inhibiting NF-κB/CBS-H 2S signaling pathway.