BACKGROUND: Abnormal iron metabolism plays a critical role in paclitaxel (PTX) resistance in esophageal cancer cells. Qige San (QG) is a traditional Chinese herbal formula that is reported to improve short-term therapeutic effects of esophageal cancer. AIM: To investigate the effects and regulatory mechanisms involved in QG-targeted PTX-resistant esophageal cancer cells. METHODS: concentration in PTX-resistant esophageal cancer cells. Expression of ferroptosis regulators was measured by western blot. Network pharmacology analysis was employed to identify potential targets of QG in PTX-resistant esophageal cancer cells. RESULTS: Treatment with QG significantly suppressed the viability, proliferation, and migration of PTX-resistant esophageal cancer cells and simultaneously induced ferroptosis. The network pharmacology analysis identified the phosphoinositide 3-kinase (PI3K)/protein kinase B signaling pathway as the potential target of QG in PTX-resistant esophageal cancer cells. Activation of the PI3K pathway notably reversed the ferroptosis of PTX-resistant esophageal cancer cells that was induced by QG. CONCLUSION: targeting the PI3K signaling pathway.