The conventional approach is time-consuming and expensive for augmenting the catalyst design and reaction conditions to enhance the yield and selectivity of the target chemicals. The combination of HTE with ML can defeat this challenge and is the way ahead to rapidly create and evaluate catalysts, leading to data-driven catalyst design. Our group has successfully demonstrated the use of the HTE-ML combination to design and evaluate the catalysts for oxidative coupling of methane, stabilizer formulation for improving polymeric material lifetime, etc. Here, we report another successful implementation of the HTE-ML approach in the design, evolution, and evaluation of multi-element catalysts for ethanol to butadiene (ETB) conversion.