This work employs (i) a rational approach to improve the material properties of catalysts for urea transesterification with ethylene glycol (EG) to ethylene carbonate (EC) over metal oxides and (ii) a statistical approach to maximize the desired product. For the rational approach, single- and mixed-metal oxides with different elemental combinations (Zn, Mg, Al, Fe) with a variety of acid–base properties were synthesized and evaluated for the reaction. The roles of acidity and basicity in the identified reaction paths were clarified on the basis of product selectivities and kinetic parameters extracted from the concentration profiles of reactants and products in every reaction path by means of in situ IR monitoring and subsequent multivariate analysis. The paths toward EC are favorably catalyzed by acidic sites, while basic sites catalyze all paths toward undesired products. However, the surface sites are blocked when the acidity is too high and there exists an optimum value for the ratio of total acidic and basic sites to be an efficient catalyst in the targeted reaction. A mixed-metal oxide consisting of Zn and Fe at a 3:1 atomic ratio was found to be the optimum catalyst with a well-balanced acid–base property. Furthermore, a design of experiments (DoE) approach was used to statistically identify critical reaction parameters and optimize them for the best Zn- and Fe-containing catalysts. These approaches successfully gave insights into the determining material factors for the reaction and afforded excellent EC selectivity (up to 99.6%) with high yield.