A cage‐based metal–organic framework (Ni‐NKU‐101) with biphenyl‐3,3’,5,5’‐tetracarboxylic acid was synthesized via solvothermal method. Ni‐NKU‐101 contains two types of cages based on trinuclear and octa‐nuclear nickel‐clusters that are connected with each other by the 4‐connected ligands, to form a 3D framework with a new topology. A mixed‐metal strategy was used to synthesize isostructural bimetallic MOFs of MxNi1‐x‐NKU‐101 (M=Mn, Co, Cu, Zn). The electrocatalytic studies showed that the hydrogen evolution reaction (HER) activity of CuxNi1‐x‐NKU‐101 is much higher than that of other MxNi1‐x‐NKU‐101 catalysts in acidic aqueous solution, owing to the synergistic effect of the bimetallic centers. The optimized Cu0.19Ni0.81‐NKU‐101 has an overpotential of 324 mV at 10 mA cm−2 and a Tafel slope of 131 mV dec−1. The mechanism of HER activity over these bimetallic MOF‐based electrocatalysts are discussed in detail.