Ni-based layered double hydroxides (LDHs), or hydrotalcite-like materials (HTs), were synthetized through co-precipitation at constant pH (NiAl and NiMg) and urea hydrolysis (NiMn) methods, and they were tested in the electrochemical methanol oxidation (MOR). The physicochemical properties were explored by using techniques such as X-ray diffraction, FT-IR spectroscopy, as well as electron paramagnetic resonance. In addition, correlation between active site arrangements and electrocatalytic activity was evidenced by density functional calculations.Specific site m(Ni 2 Mn-OH) showed the lowest proton energy removal at approximately 3.6 eV and the NiMn LDH sample containing a higher proportion of this site exhibited the best performance for the MOR process, with an enhancement factor of 5.16, which is attributed to limited deactivation of Ni during the reaction. CO 2 production was detected by differential electrochemical mass spectrometry to be on the order of ten times greater than O 2 .