Objectives <p>Cancer cells are addressed through conventional chemotherapy, resulting in tumour resistance and systemic toxicities affecting organ functions. Nanoparticle (NPs) represent a promising approach to improve chemotherapeutic efficacy and reduce adverse effects. This study aims to improve hepato-renal function by dichloroacetate nanoparticles (DCA-PNPs) and doxorubicin (Dox) combinatorial treatment in Ehrlich ascites carcinoma (EAC) model.</p> Results <p>Dichloroacetate nanoparticles characterizations showed effective drug encapsulation, optimal particles size, morphology, and distribution. Biochemical analysis showed normalized protein content, improved lipid profile, enhanced liver, kidney functions, antioxidant activity, and decreased oxidative-stress with Dox/DCA-PNPs combination treatment, indicating that NPs-based therapy enhanced therapeutic outcomes and minimized systemic toxicity via mitigated Dox side effects and maintained organ's function. This study elucidates that Dox/DCA-PNPs combination therapy provides a more effective strategy for EAC hepatorenal function improvements.</p> Graphical Abstract <p></p>