Abstract The standard regimen of gemcitabine combined with cisplatin offers limited clinical benefits in the treatment of advanced intrahepatic cholangiocarcinoma (ICC) due to intrinsic or acquired resistance. Currently, effective biomarkers to predict and improve chemotherapy resistance in ICC are lacking. Here, it is reported that a long non‐coding RNA (lncRNA), PAX8‐AS1 , reduces the efficacy of standard chemotherapeutic drugs. Mechanistically, PAX8‐AS1 activates NRF2 by binding to p62, thereby promoting GPX4 transcription, and stabilizes GPX4 mRNA through interaction with IGF2BP3. The PAX8‐AS1 /GPX4 axis inhibits ferroptosis and promotes resistance to gemcitabine and cisplatin. In preclinical models, the combination of the GPX4 inhibitor JKE‐1674 with gemcitabine and cisplatin exhibits superior antitumor efficacy. These findings suggest a promising therapeutic strategy to improve chemotherapy efficacy in advanced ICC.