<p>Silybin, a potent hepatoprotective flavonolignan, exhibits poor aqueous solubility, low intestinal permeability, and extensive first-pass metabolism, resulting in limited oral bioavailability. The present study aimed to develop silybin-loaded deoxycholic acid-modified chitosan-lecithin nanoparticles (DCS-LC NPs) as an oral nanocarrier system to enhance intestinal absorption and hepatoprotective efficacy. Amphiphilic deoxycholic acid-grafted chitosan was synthesized and nanoparticles were prepared by ionic gelation technique followed by optimization using Box-Behnken Design. The optimized DCS-LC NPs exhibited nanosized particle distribution, high entrapment efficiency, favourable zeta potential, sustained pH-responsive drug release, and good colloidal stability. Solid-state characterization confirmed successful drug encapsulation within the lipid-polymer matrix. The nanoparticles also demonstrated excellent hemocompatibility and cytocompatibility in haemolysis and MTT assays. Ex vivo permeability studies showed significantly enhanced intestinal permeation compared with pure silybin and unmodified chitosan nanoparticles. Pharmacokinetic studies revealed markedly improved systemic exposure with approximately 2.9-fold enhancement in C_max and &gt; 11-fold increase in AUC. Moreover, in a CCl₄-induced hepatotoxicity model, DCS-LC NPs significantly improved hepatoprotective activity by restoring hepatic biochemical markers and reducing liver injury. Overall, the developed nanoparticulate system represents a promising oral delivery platform for improving the bioavailability and therapeutic efficacy of silybin.</p> Graphical Abstract <p></p>