Cysteine protease inhibitor S (CST4) plays a pivotal role in the regulation of growth, invasion, and metastasis of a variety of malignancies. However, the potential mechanism behind how CST4 contributes to CST4 in lymph node metastasis (LNM) and tumor-associated lymphangiogenesis of esophageal cancer (EC) cells has not been elucidated previously. Short hairpin RNA technique was utilized to upregulate the CST4 gene expression. Different experiments, including the tubule formation assay and immunofluorescence, were conducted to observe the cellular behavior. Enzyme-linked immunosorbent assay (ELISA) and Western blot analyses were employed to determine the expression levels of relevant proteins. In our study, we discovered that high expression of CST4 in EC cells had multiple effects. It stimulated cell proliferation, invasion, and migration and caused epithelial-mesenchymal transition (EMT). Moreover, it also inhibited the apoptosis of EC cells and caused them to stagnate in the G2/M phase. High expression of CST4 promoted the secretion of lymphangiogenic markers (TGFβ1, VEGF, VEGF-C/D) in EC cells. In addition, high expression of CST4 in EC cells not only enhanced the proliferation and migration of HLECs, but also stimulated the lumen formation and F-actin expression and rearrangement of HLECs. The elevated expression of CST4 also facilitated the secretion of p-ERK1/2, MMP9, and MMP-2 in HLECs. However, various tumor-promoting effects of high expression of CST4 on HLECs could be inhibited by VEGF inhibitors in EC cells. Overall, our findings indicate that CST4 plays a significant role in the accumulation, migration, and EMT of EC cells. CST4 can activate the VEGF-MAPK/ERK-MMP9/2 signaling axis to promote LNM and lymphangiogenesis in EC.