Hirschsprung disease (HSCR) is a common peripheral neurodevelopmental disorder and impaired enteric neural crest cell migration is one of the key factors. Secretagogin (SCGN) has been demonstrated to play a critical role in the rostral migratory stream during central nerve regeneration. However, there is a paucity of knowledge on the role of SCGN in enteric neural crest cell migration. Here, we revealed a significant downregulation of SCGN by protein profiles using tandem mass tag in HSCR lesion colon tissues. We identified decreased expression of SCGN could hinder cell migration in vitro and in vivo. Mechanistically, SCGN upregulated the transcription factor (lymphoid enhancer-binding factor 1 [LEF-1]), which directly activated the transcription of the cell adhesion molecule (neural cell adhesion molecule 1 [NCAM1]), thereby promoting cell migration. In conclusion, this study elucidates the role of SCGN in HSCR pathogenesis by demonstrating its involvement in affecting neural crest cell migration through the lymphoid enhancer-binding factor 1/neural cell adhesion molecule 1 axis. The findings could contribute to the diagnostic and therapeutic strategies for HSCR.