Understanding the catalytic activity of high-entropy alloys (HEAs) toward the conversion of small molecules such as carbon monoxide (CO) can provide insight into their structure-property relations. The identification of specific descriptors that govern the CO oxidation on HEAs is crucial to design new materials with customized compositions and structures. Herein, we have rationally assessed the CO oxidation mechanism on an extended AgAuCuPdPt HEA electrocatalyst under an acidic electrolyte. We compare the HEA performance with respect to platinum (Pt), palladium (Pd), and gold (Au) monometallic surfaces for CO oxidation. We also evaluated the same reaction on a binary AuPd alloy and a quaternary AuCuPdPt polycrystalline alloy with the aim of understanding the surface composition effects of the HEA. To provide insights into the descriptors controlling the CO oxidation mechanism and overpotential of the different alloy chemistry, we have combined cyclic voltammetry, surface-sensitive characterisation techniques and density functional theory (DFT) simulations. We show that silver (Ag) can improve the catalytic oxidation of CO by perturbing the *OH adsorption energy of Pd, leading to a lower onset potential. Additionally, we observed that Au segregates on the surface and that Cu is not stable at high applied potentials after CO oxidation. We highlight that HEA electrocatalysts are a valuable platform for designing more active and selective electrocatalyst surfaces.