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This study aims to enhance the antidiabetic potential of Vanadium pentoxide (V 2 O 5 ) by synthesizing chitosan-based nanoparticles (NPs). Chitosan and its derivatives were used to fabricate V 2 O 5 NPs, ensuring enhanced antioxidant and antidiabetic activity. Surface topography was analyzed using atomic force microscopy (AFM), revealing bioactive sites on the NPs with improved electron-transfer capability, as confirmed by cyclic voltammetry (CV). Furthermore, NPs were exploited for their possible antioxidant and antidiabetic potency by using different in-vitro assays. Among the fabricated NPs, chitosan-salicylaldehyde decorated V 2 O 5 NPs (CHVD 2 ) exhibited highest antidiabetic activity with 72.69 ± 0.76 % inhibition against α-amylase, 69.15 ± 0.58 % inhibition against α-glucosidase, and glycemic diffusion retardation index (GDRI) of 60.33 ± 0.47 %. Importantly, CHVD 2 did not inhibit the growth of Bifidobacterium bacteria, as shown by disc-diffusion assay and exhibit least cytotoxicity among all NPs as tested on HacaT cell line. Molecular docking studies revealed strong binding interactions between CHVD 2 and the target enzymes, α-amylase, and α-glucosidase supporting its inhibitory potential. This work demonstrates the promising enhanced antidiabetic and antioxidant properties of chitosan-coated V 2 O 5 NPs., Competing Interests: Declaration of competing interest All authors declare that there is no competing interest associated with this research article., (Copyright © 2025 Elsevier B.V. All rights reserved.)