Vanadium phosphorus oxide (VPO) catalysts were developed for the aldol condensation of methyl acetate (MeOAC) with formaldehyde (HCHO) to methyl acrylate (MA). The influence of P/V ratio on catalytic activity and selectivity was revealed and optimized with a fixed bed reactor. The controllable preparation of VPO catalyst was reached, and the influence of carrier gas on the resistance of carbon deposition was also systematically investigated. Response surface methodology (RSM) with three independent variables of molar ratio of MeOAC to HCHO, space velocity, and reaction temperature was employed to optimize MA yield with VPO catalysts. The high value of R-squared presented a reasonable correlation of regression model to the experimental data. Lastly, the kinetics of aldol condensation to produce MA over VPO catalyst was studied.