Hepatocellular carcinoma is one of the leading causes of cancer deaths globally and a key hindrance to extending life expectancy. Celastrol (CEL) demonstrates excellent antitumor activity, but faces challenges like low solubility and a narrow therapeutic window, limiting its clinical application. To address these limitations, drug combinations and nano-delivery systems have emerged as effective solutions. Curcumin (CUR), known for its antitumor and hepatoprotective effects, also exhibits good biocompatibility and the ability to mitigate drug-induced liver injury. Considering the complementary properties of CEL and CUR, including CEL's potent antitumor activity and CUR's hepatoprotective effects, we developed a novel self-assembling nanodrug delivery system (CCPN) for the co-loading of both compounds. CCPN nanoparticles were constructed through non-covalent interactions, including hydrogen bonding, π-π stacking, and electrostatic forces, which confer good stability and significantly enhance the solubility and bioavailability of CEL and CUR. Extensive in vitro and in vivo experiments demonstrated that CCPN effectively reduced CEL-induced hepatotoxicity in zebrafish and mouse models, exhibiting good biosafety. Additionally, CUR's fluorescence provides a unique advantage for real-time monitoring of drug distribution and release, facilitating the tracking of therapeutic progress. Furthermore, CCPN nanoparticles enhanced delivery efficiency in HepG2 cells, exhibiting superior anti-liver tumor outcomes, which are associated with the promotion of apoptosis in tumor cells. This study presents CCPN as a promising therapeutic strategy for hepatocellular carcinoma, integrating reduced hepatotoxicity, self-monitoring capabilities, and superior therapeutic efficacy.