Hydrogen pickup and embrittlement pose a challenging safety limit for structural alloys used in a wide range of infrastructure applications, including zirconium alloys in nuclear reactors. Previous experimental observations guide the empirical design of hydrogen-resistant zirconium alloys, but the underlying mechanisms remain undecipherable. Here, we assess two critical prongs of hydrogen pickup through the ZrO 2 passive film that serves as a surface barrier of zirconium alloys; the solubility of hydrogen in it-a detrimental process-and the ease of H 2 gas evolution from its surface-a desirable process. By combining statistical thermodynamics and density-functional-theory calculations, we show that hydrogen solubility in ZrO 2 exhibits a valley shape as a function of the chemical potential of electrons, μ e . Here, μ e , which is tunable by doping, serves as a physical descriptor of hydrogen resistance based on the electronic structure of ZrO 2 . For designing zirconium alloys resistant against hydrogen pickup, we target either a dopant that thermodynamically minimizes the solubility of hydrogen in ZrO 2 at the bottom of this valley (such as Cr) or a dopant that maximizes μ e and kinetically accelerates proton reduction and H 2 evolution at the surface of ZrO 2 (such as Nb, Ta, Mo, W, or P). Maximizing μ e also promotes the predomination of a less-mobile form of hydrogen defect, which can reduce the flux of hydrogen uptake. The analysis presented here for the case of ZrO 2 passive film on Zr alloys serves as a broadly applicable and physically informed framework to uncover doping strategies to mitigate hydrogen embrittlement also in other alloys, such as austenitic steels or nickel alloys, which absorb hydrogen through their surface oxide films.