It has previously been reported that under high-pressure V2O5 (α-V2O5) transforms into a layered polymorph, β-V2O5, consisting of V5+O6 octahedra instead of V5+O5-square pyramids. Both polymorphs have a good performance as positive electrode for lithium batteries. In this work, we investigate the pressure-induced α → β transformation combining first principles and experimental methods. Density functional theory (DFT) predicts that α-V2O5 transforms to β-V2O5 at 3.3 GPa with a 11% volume contraction; experiments corroborate that at a pressure of 4 GPa, V2O5 (d = 3.36 g/cm3) transformed into a well-crystallized β-V2O5, with a much denser structure (d = 3.76 g/cm3). β-V2O5 can be also prepared at 3 GPa, although with a substantial degree of amorphization. The calculated bulk modulus of α-V2O5 (18 GPa) indicates that this is a very compressible structure; this being linked to the contraction along its b-axis (interlayer space) and to a significant decrease of a long V−O distance (V−O ≈ 2.9 Å). As a result, the vanadium coordination increases from five (square pyrmamid) in α-V2O5 to six (distorted octahedron), leading to the stabilization of the high-pressure (β) polymorph. This change of the coordination environment of vanadium ions also affects the electrical conductivity. The calculated density of states shows a narrowing of 0.5 V in the band gap for the β polymorph, in comparison to the ambient-pressure material; the measured resistivities at room temperature (10 000 Ω cm in α-polymorph and 400 Ω cm in β-polymorph) reveal that β-V2O5 is indeed a better electronic conductor than α-V2O5. In view of these results, similar transformations at moderate pressures are expected to occur in other V5+ frameworks, suggesting an interesting way to synthesize novel V5+ compounds with potential for electrochemical devices.