Abstract: This study presents the design and evaluation of a medium entropy alloy (MEA), Ti21Zr21Fe41Ni17, for hydrogen storage at room temperature (30 °C), employing an integrated design approach that combines CALPHAD calculations with semiempirical rules. The alloy was developed based on four specific design criteria: (1) valence electron concentration (VEC) between 6.2 and 6.5, (2) atomic size mismatch (d) of at least 9.7%, (3) an atomic radius ratio of hydride-forming to non-hydride-forming elements (rA/rB) ranging from 1.149 to 1.219, and (4) stability of the C14 Laves phase as the primary phase, as confirmed by CALPHAD. The resulting alloy crystallized predominantly in the C14 Laves phase (92.8 wt %), with a minor body-centered cubic (BCC) phase. Transmission electron microscopy (TEM) results revealed coherent nanograin boundaries, particularly at the C14/BCC interphase, facilitating rapid hydrogenation kinetics. After a one-step simple thermal activation, the alloy reversibly absorbed 1.4 wt % of hydrogen with relatively low hysteresis and fast kinetics, attributed to a preferential hydride nucleation at grain boundaries. In terms of thermodynamic properties, the chemical composition, designed according to the aforementioned criteria, should be considered, with the high iron content (41%) playing a critical role. The high atomic percentage of iron, a non-hydride-forming element, stabilizes the C14 phase due to the significant negative contribution of the interaction parameter (Oij) of the Fe–Zr pair (Oij = -118.4 kJ/mol), which results in a negative enthalpy of mixing in the C14 structure. This work underscores the utility of combining CALPHAD and semiempirical design methods while outlining critical challenges and future directions for optimizing MEAs for hydrogen storage Ver menos