Cholangiocarcinoma (CCA) or bile-duct cancer is most prevalent in Southeast Asian counties including Thailand. Patients present at an advanced stage when the cancer is often drug resistant, leading to chemotherapy failure. Curcumin has therapeutic potential with various anticancer properties. However, its effectiveness is limited by its low bioavailability, poor solubility, and instability. This study aimed to synthesize, characterize and evaluate the efficacy of curcumin-loaded maltodextrin-based proniosomes (CMPNs) to overcome the limitations of curcumin for treating gemcitabine-resistant CCA cells (KKU-213B) in vitro and in vivo Various proniosome formulations were developed and tested for their efficacy against KKU-213B cells using cytotoxicity, clonogenic, migration, and invasion assays. The potential mechanism involving in cell cycle arrest, apoptosis, expression of C/EBP homologous protein (CHOP), a pro-apoptotic transcription factor, and other apoptotic markers were investigated. The results showed that nanoscale CMPNs exhibited a good curcumin loading capacity and an entrapment efficiency of over 97%, as well as good stability and permeability through porcine esophageal mucosa. CMPNs inhibited proliferation, colony formation, migration/invasion and induced apoptosis in KKU-213B cells. Western blot analysis revealed CMPNs significantly increased CHOP, the cleavage products of poly(ADP-ribose) polymerase-1 (PARP-1), apoptosis-inducing factor, and caspase-3 expression in KKU-213B cells. A xenograft model revealed that 62.5 mg/kg BW CMPNs significantly suppressed proliferating cell nuclear antigen and increased CHOP-mediated apoptosis, leading to significantly reduced tumor volume. In conclusion, CMPNs effectively overcome limitations of curcumin and offer an effective strategy against gemcitabine-resistant CCA via CHOP-mediated pathways. These proniosomes are promising as an alternative treatment approach for CCA.