Lead (Pb) is a typical heavy metal in the flue gas of coal-fired power plants, which can cause the deactivation of SCR catalysts. In this study, Pb-doped vanadium-based catalysts were prepared and investigated for the deactivation effect and mechanism of elemental Hg oxidation caused by Pb. The results showed that doping Pb on vanadium-based catalysts led to severe deactivation, which was more pronounced with increased Pb content. Further investigation illustrated that the introduction of Pb not only weakened the BET surface properties of vanadium-based catalysts but also increased the aggregation of surface species on the catalysts. After Pb introduction, the adsorption capacity toward elemental Hg, proportion of highly oxidized V5+, and surface Oβ ratio significantly decreased severely weakening the activity of the catalyst. In addition, we demonstrated that the reaction between Pb and active VO/V−OH groups of the catalyst formed inactive V−O−Pb species, which was the direct cause of catalyst deactivation.