The development of cost-effective catalysts for hydrogen evolution reaction (HER) and hydrogen oxidation reaction (HOR) is the key to realizing alkaline fuel cells and water electrolytic cells applications. Early reports have shown that surface modification of Pt-based catalysts with highly oxygenophilic metals can significantly enhance their HOR/HER activity. Here, we successfully synthesized uniform trimetallic PdPtNi hollow nanocages (PdPtNi HNCs) with excellent HER and HOR activity under alkaline media via hydrothermal deposition of oxygenophilic Ni on PdPt HNCs. Moreover, the PdPtNi HNCs exhibit superior HER/HOR durability and excellent CO-tolerance in HOR, compared with commercial Pt/C catalyst. The theoretical calculations confirm that the introduced Ni enriched the electronic and balanced the interactions of the adsorbed intermediates (OH_ad and H_ad) on the catalyst’s surface, thus promoting the HER and HOR activity. This work provides a promising approach for designing and synthesizing bifunctional and highly efficient catalysts.