A design-of-experiments approach for the investigation of the cross-metathesis of methyl ricinoleate with methyl acrylate is described. Two second-generation metathesis initiators were studied using different reaction conditions, revealing optimal reaction conditions for each catalyst. Interestingly, the two catalysts showed completely different temperature response profiles. As a result of these investigations, suitable reaction conditions for the sustainable production of two value-added chemical intermediates were derived. Moreover, the design-of-experiments approach provided valuable information for a thorough understanding of catalytic reactions that would be more difficult to obtain by classic approaches.