Vanadium pentoxide (V2O5) offers high capacity and energy density as a cathode candidate for lithium-ion batteries (LIBs). Unfortunately, its practical utilization is intrinsically handicapped by the low conductivity, poor electrode kinetics, and lattice instability. In this study, the synergistical optimization protocol has been proposed in the conjunction of interstitial Ca incorporation and organic vanadate surface protection. It is revealed that regulating Ca occupation in the body phase at a relatively low concentration can effectively expand the layer distance of α-V2O5, which facilitates the intercalation access for Li-ion insertion. On the other hand, organometallics are first applied as the protective layer to stabilize the electrode interface during cycling. The optimized coating layer, vanadium oxy-acetylacetonate (VO(acac)2), plays an important role to generate a more inorganic component (LiF) within the solid electrolyte interface, contributing to the protection of the Ca-incorporated V2O5 electrode. As a result, the optimized Ca0.05V2O5/VO(acac)2 hybrid electrode exhibits much improved capacity utilization, rate capability, and cycling stability, delivering capacity as high as 297 mAh g-1 for full LIBs. The first-principle computations reveal the lattice change caused by the Ca incorporation, further confirming the lattice advantage of Ca0.05V2O5/VO(acac)2 with respect to Li-ion intercalation.