Pancreatic malignancies rank among the most aggressive and fatal carcinomas in modern oncology, presenting significant therapeutic challenges due to their inherent chemoresistance. In the context of our experimental investigations, we have developed a mitochondria-targeted hydrogel formulation, termed SWMU690@PUE, which demonstrates the ability to modulate mitochondrial homeostasis effectively. The hydrogel construct was precisely designed via the spontaneous supramolecular assembly of puerarin (PUE) and SWMU690 components, facilitated under carefully controlled thermodynamic conditions. Comprehensive in vitro analyses of the SWMU690@PUE complex were conducted to rigorously evaluate its efficacy in regulating mitochondrial homeostasis. The experimental findings revealed that SWMU690@PUE exhibited pronounced selectivity for mitochondrial targeting, subsequently diminishing mitochondrial membrane potential-a pivotal parameter in cellular bioenergetics. Our study further demonstrated that SWMU690@PUE effectively mitigates the chemoresistance phenotype associated with mitochondrial dysfunction. This therapeutic potential was exemplified by its capacity to induce mitochondria-mediated apoptotic and ferroptotic cell death, critical oncocidal pathways, in pancreatic carcinoma cells across both in vitro and in vivo models. Additionally, SWMU690@PUE displayed significant antineoplastic activity, as evidenced by its robust inhibition of pancreatic cancer cell proliferation in both experimental frameworks. In conclusion, this study presents an innovative therapeutic approach specifically designed to overcome the persistent challenge of chemoresistance in the treatment of pancreatic neoplasms.© 2025 The Authors.