Polyoxymethylene dimethyl ethers (PODEn) converted from methanol and formaldehyde were investigated with alumina supported ZrO2 catalyst in a stainless steel tube fixed-bed reactor within the temperature range from 333 to 433 K and the pressure range from 0.1 to 2.5 MPa. First, results from catalytic performance tests showed that the catalyst gamma-Al2O3 containing 4 mol % ZrO2 exhibited the highest activity for PODEn synthesis. The stoichiometry analysis of raw material indicated that ZrO2 modified catalyst had the optimum activity at methanol/formaldehyde = 3 (mol/mol). An increase of the reaction pressure resulted in a significant increase in methanol conversion from 13.18 to 48.64%, and selectivity to PODE3-8 was enhanced to 24.82%. The temperature experiment analysis confirmed the optimization of the reaction temperature to be 393 K. Second, SEM and TEM showed the relationship between the catalytic activity and the catalyst-crystal alignment. Incorporation of ZrO2 in the framework of gamma-Al2O3 was noticed and confirmed by X-ray diffraction (XRD) and BET analysis. The NH3-TPD tests indicated the relationship between catalytic activity and acidity. Finally, an elimination mechanism was proposed to explain the PODEn synthesis reaction rate and kinetic model. The contributions of intraparticle and external diffusion were eliminated by changing the size of catalyst particles and space velocity. The proposed model can reasonably predict the observed behaviors of PODEn synthesis from methanol and formaldehyde.