Background <p>Cisplatin resistance significantly limits the effectiveness of chemotherapy in esophageal squamous cell carcinoma (ESCC). Understanding the molecular mechanisms driving resistance is essential for improving treatment outcomes.</p> Objective <p>This study aimed to investigate the role of the FOXK1/AKT2 axis in cisplatin resistance in ESCC cells and to evaluate the potential of triptonide in reversing this resistance.</p> Methods <p>Cisplatin sensitivity was assessed in ESCC cell lines with altered FOXK1 expression. A cisplatin-resistant TE1 cell line (TE1-R) was established by prolonged low-dose cisplatin exposure. Luciferase reporter assays were conducted to determine whether FOXK1 activates AKT2 transcription. Cell viability, colony formation, apoptosis assays, and expression analysis of apoptosis-related genes were performed to examine the effects of FOXK1, AKT2, and triptonide.</p> Results <p>FOXK1 overexpression reduced cisplatin sensitivity in ESCC cells, while FOXK1 knockdown restored sensitivity in TE1-R cells. FOXK1 directly enhanced AKT2 transcription by binding to its promoter region. The FOXK1/AKT2 axis promoted cell proliferation and suppressed cisplatin-induced apoptosis. Triptonide treatment downregulated FOXK1 and AKT2 expression, inhibited proliferation, induced apoptosis, and sensitized ESCC cells to cisplatin in a synergistic manner.</p> Conclusions <p>The FOXK1/AKT2 signaling axis contributes to cisplatin resistance in ESCC. Triptonide reverses resistance by inhibiting this axis, offering a promising strategy to enhance cisplatin efficacy in ESCC therapy.</p>