In the current study, alloxan-induced diabetic mice model was used to assess the antihyperglycemic effects of Chitosan Nanoparticles (CSNP) loaded with (Punica granatum methanol extract-PG) bioactive compounds. Analysis of P. granatum extract revealed significant concentrations of various classes of polyphenols. In particular, the total polyphenols content is noted at 289.6 ± 5.1 mg/g, while flavonoids and anthocyanins exhibited concentrations of 53.7 ± 0.8 mg/g and 34.8 ± 0.4 mg/g, respectively. Chitosan nanoparticles were prepared by ionic gelation technique using TPP as crosslinking agent. Their spectroscopic characterization showed a good stability, high encapsulation efficiency and the bioactive molecule-loaded CNPs were well-dispersed with homogeneous distribution in the nanosolutions. In vivo experiments showed that when compared to the diabetic control group, diabetic mice treated with CSPG-CNP (100 mg/kg bw) displayed a significant decrease in their mean fasting blood glucose levels. Moreover, hepatic and kidneys histopathological examination showed clear improvements in hepatic alterations in animals treated with CSPG-CNP compared to diabetic control group. Indeed, hepatic cells regained normal size, hepatic steatosis decreased, and the number of inflammatory cells was drastically reduced, suggesting effectiveness of this combination in improving diabetes-induced hepatic lesions. Moreover, mice of CSPG-CNP group showed significant improvements in renal alterations with signs of renal tissue repair. Indeed, damage to Bowman's capsule, glomeruli, and renal tubules were improved, returning to normal renal histology.