In this study, CNCs were extracted from durian rind. Modification to CNCs with saponin was conducted at 50 °C for one h. CNCs and CNCs-saponin were employed as dexamethasone carriers. Modification to CNCs using saponin did not change the relative crystallinity of CNCs. CNCs’ molecular structure and surface chemistry did not alter significantly after modification. Both nanoparticles have surface charges independently of pH. Dexamethasone-released kinetics were studied at two different pH (7.4 and 5.8). Higuchi, Ritger–Peppas, first-order kinetic and sigmoidal equations were used to represent the released kinetic data. The sigmoidal equation was found to be superior to other models. The CNCs and CNCs-saponin showed burst release at 30 min. The study indicated that cell viability decreased by 30% after modification with saponin.