Role of V2O5 as a strong network glass modifier on the optical, elastic, physical, and radiation protection performance of V2O5-based glasses in form 10CaF2-(20-x)Bi2O3-60P2O5-10B2O3:xV2O5, x = 0.0, 0.5, 1.0, 1.2, 0.2, and 2.5 mol% was investigated in this article. The studied glasses have been synthesized using the melt-quenching technique. The investigated samples coded as V0, V1, V2, V3, V4, and V5 according to x values. Difference theoretical approaches have been utilized to achieve these goals including: radiation shielding calculations, optical, and elasto-mechanical properties. The optical basicity (Λ(Eg)) was found to decrease from 0.5630 to 0.5593 with increasing the mol% of [V4+] in the glass samples. The density was decreased from 4.134 to 3.817 g cm−3 associated with a simultaneous decrease in the oxygen molar volume (OMV) from 12.5 to 12.25 cm3/mol as the mol% of [V4+] increased in the samples. The Vicker’s hardness was found to be diminished with increasing V2O5 content in the investigated glasses. All elastic moduli were reduced as V2O5 increased. Refractive index increased from 2.20 to 2.63, while metallization criterion decreased from 0.341 to 0252. The observed trend of mass attenuation coefficient (MAC) values in the tested energy spectrum followed the sequence: (MAC)v0 > (MAC)v1 > (MAC)v2 > (MAC)v3 > (MAC)v4 > (MAC)v5. Also, we found that linear attenuation coefficient (LAC) increased, while the half value layer (HVL), and transmission coefficient (TF%) were also decreased. The HVL values of the current samples were compared with standard glasses, and it found that V2O5-based samples possess a comparable photon protection capacity as commercial RS-360 and RS-520 glasses. © 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.