The reaction mechanism of methanol oxidation catalyzed by vanadium oxides on a silica support (V2O5/SiO2) was investigated in a high-throughput operando reactor coupled with a Fourier transform-infrared (FT-IR) imaging system for rapid product analysis and six parallel, in situ Raman spectroscopy probes for catalyst characterization. Up to six V2O5/SiO2 catalysts with different vanadium loadings (i.e., from 0 to 7%) were simultaneously monitored under identical experimental conditions. The specific Raman bands of the different catalysts in the six parallel reaction channels are quantitatively determined in this work. Under steady-state reaction conditions, the Raman intensities of C–H stretch in Si–O–CH3 and V–O–CH3 were extensively studied at different reaction temperatures and different vanadium loadings. For the first time, we observed enhanced Si–O–CH3 formation on V2O5/SiO2 catalysts with low vanadium loadings. We attribute this phenomenon to surface cluster edge activation. Careful comparison of the in situ Raman intensity of V–O–CH3 on V2O5/SiO2 catalysts revealed different methoxy formation mechanisms in different reaction temperature regimes.