Vanadium (V) is sensitive to minute quantity of oxygen interstitials, which induce pronounced hardening and embrittlement. Here, we utilize oxygen to synthesize V solid solutions in order to reveal the mechanism of oxygen solutes induced hardening. With increasing of oxygen solute concentrations, the fracture modes of V samples transform from dimple, to a mixture of dimple and cleavage, and to a fully transgranular cleavage. High density of dislocations and dislocation debris are produced in strained samples. The mobility of screw dislocations is reduced and the dislocation cross-slip events are promoted by oxygen solutes. In addition to oxygen solution hardening, the generation of high density of oxygen-vacancy complexes plays a dominant role in the strengthening. High quantity of loop-shaped dislocation debris are direct evidence for the formation of oxygen-vacancy complexes. Profuse oxygen-vacancy complexes trap dislocations, promote cross-slips and assist dislocation storage, thus give rise to a superior combination of strengthening, strain hardening, and ductility in V with 1.0 at% of oxygen. Once beyond a critical oxygen concentration (>1.6 at%), V shows catastrophic brittle failure due to the exceptional high density of oxygen-vacancy complexes. These findings provide insight to design high performance refractory metals utilizing oxygen solutes.