The present paper is aimed at determining the less investigated effects of hydrogen uptake on the microstructure and the mechanical behavior of the oxidized Zircaloy-2 alloy. The specimens were oxidized and charged with hydrogen. The different oxidation temperatures and cathodic current densities were applied. The scanning electron microscopy, X-ray electron diffraction spectroscopy, hydrogen absorption assessment, tensile, and nanoindentation tests were performed. At low oxidation temperatures, an appearance of numerous hydrides and cracks, and a slight change of mechanical properties were noticed. At high-temperature oxidation, the oxide layer prevented the hydrogen deterioration of the alloy. For nonoxidized samples, charged at different current density, nanoindentation tests showed that both hardness and Young’s modulus revealed the minims at specific current value and the stepwise decrease in hardness during hydrogen desorption. The obtained results are explained by the barrier effect of the oxide layer against hydrogen uptake, softening due to the interaction of hydrogen and dislocations nucleated by indentation test, and hardening caused by the decomposition of hydrides. The last phenomena may appear together and result in hydrogen embrittlement in forms of simultaneous hydrogen-enhanced localized plasticity and delayed hydride cracking.