The aim of this study was to analyse the anti-esophageal squamous cell carcinoma (ESCC) effects of Trichosanthes kirilowii Maxim. (TkM) using network pharmacology and experimental verification. A 'compound-target-ESCC'network was constructed to screen the main active components, targets and potential mechanisms of action of TkM anti-ESCC. The proliferation of human esophageal carcinoma TE-1 cell treated with TkM extract was detected by CCK8 and plate cloning, the migration of cells was detected by cell scratching, and the apoptosis of cells was detected by flow cytometry and Western blot. The main active components of TkM anti-ESCC action include diosmetin, hydroxygenkwanin, cucurbitacin B, etc., which are involved in the targets of BCL2, NR3C1, STAT3, PGR, and PTGS2, which are involved in several biological processes such as the regulation of cellular proliferative activity, cellular programmed response, and lipid metabolism. In addition, TkM effectively inhibited the proliferative activity and migration rate of TE-1 in vitro and promoted apoptosis. These findings suggest that the anti-ESCC effect of TkM is based on the synergistic and complex action of multiple components, targets and pathways. TkM may target BCL2 as a drug and induce early apoptosis in TE-1 cells through endogenous pathways.