Vanadium-substituted phosphomolybdic acids (H3+x[PMo12-xVxO40], denoted as Vx) are well-known oxidation catalysts that are generally prepared by the hydrothermal treatment of MoO3 and V2O5 in the presence of H3PO4. This synthesis procedure is highly energy consuming and the Vx yields are not always acceptable. In the present work, an alternative hybrid mechanochemical/hydrothermal synthesis of Vx is proposed, comprising the ball-milling of MoO3 and V2O5, followed by a hydrothermal attack. The resulting materials, with 2 ≤ x ≤ 3, obtained from this new route were compared, in terms of yield, energy consumption and catalytic activity, with a reference V3 sample prepared through a conventional hydrothermal treatment. The ball-milling step proved to lead not only to a shorter and far more energy-saving synthesis procedure, but also to high yields of Vx. Moreover, Vx from this alternative route proved to be generally more active than the conventionally prepared V3 in the aerobic oxidative cleavage of C-O and C-C bonds in 2-phenoxyacetophenone, used herein as a lignin model compound.