The revolutionary development of machine learning and data science and exploration of its application in material science are huge achievements of the scientific community in the past decade. In this work, we have reported an efficient approach of machine learning-aided high-throughput screening for finding selective earth-abundant high-entropy alloy-based catalysts for CO to methanol formation using a machine learning algorithm and microstructure model. For this, we have chosen earth-abundant Cu, Co, Ni, Zn, and Mg metals to form various alloy-based compositions (bimetallic, trimetallic, tetrametallic, and high-entropy alloys) for selective CO reduction reaction toward CHOH. Since there are several possible surface microstructures for different alloys, we have used machine learning along with DFT calculations for high-throughput screening of the catalysts. In this study, the stability of various 8-atom fcc periodic (111) surface unit cells has been calculated using the atomic-size difference factor (δ) as well as the ratio taken from Gibbs free energy of mixing (Ω). Thinking about the simplicity and accuracy, microstructure models by considering the neighboring atoms of the adsorption sites and others as Cu atoms have been considered for different adsorption sites (on-top, bridge, and hollow-hcp). Moreover, the adsorption energies of the *H, *O, *CO, *HCO, *HCO, and *HCO intermediates have been predicted using the best fitted algorithm of the training set. The predicted adsorption energies have been screened based on the pure Cu adsorption energy. Furthermore, the screened catalysts have been correlated among different adsorption site microstructures. At the end, we were able to find seven active catalysts, among which two catalysts are CuCoNiZn-based tetrametallic, three catalysts are CuNiZn-based trimetallic, and two catalysts are CuCoZn-based trimetallic alloys. Hence, this work demonstrates not an ultimate but an efficient approach for finding new product-selective catalysts, and we expect that it can be convenient for other similar types of reactions in forthcoming days.