This study investigates the role of SPINK1 in liver cancer and its regulatory relationship with FOXM1. Using differential gene analysis in the GEO database, SPINK1 was identified as overexpressed in liver cancer tissues and associated with poor prognosis, confirmed via PCR. Functional assays demonstrated that SPINK1 knockdown reduced proliferation, migration, and invasion in liver cancer cells, while promoting apoptosis. In vivo experiments revealed that SPINK1 knockdown inhibited tumor growth, decreased Ki-67 and N-cadherin levels, increased E-cadherin levels, and suppressed lung metastasis. Analysis of upstream factors indicated that FOXM1 binds to the SPINK1 promoter, as validated by dual-luciferase and ChIP assays, thereby promoting SPINK1 transcription. TCGA database analysis and clinical tissue validation showed that FOXM1 expression correlates with poor prognosis in liver cancer. Functional studies demonstrated that FOXM1 knockdown suppressed liver cancer progression, while SPINK1 overexpression reversed these effects. KEGG enrichment analysis identified the p53 pathway as a key downstream target of SPINK1, and Western blotting confirmed its role in modulating p53 pathway activity. These findings reveal a critical FOXM1-SPINK1 axis in liver cancer progression. FOXM1 directly promotes SPINK1 transcription, enhancing tumor cell proliferation and metastasis while regulating the p53 pathway. Targeting this axis could provide a potential therapeutic approach for liver cancer.