<p>In this study, we propose an effective strategy for selecting alloying elements to suppress hydrogen diffusion in <i>γ</i>-uranium (<i>γ</i>-U) based on the first-principles investigation of the Niobium (Nb) influences on hydrogen diffusion behavior. The simulation results show that the substitution of Nb in the body-centered cubic (bcc) lattice of <i>γ</i>-U significantly reduces the hydrogen diffusion rate, driven by two key factors: the thermodynamic stabilization of the <i>γ</i>-U bcc lattice and Nb’s strong hydrogen trapping effect. Diffusion energy pathway and electronic structure analyses reveal the presence of energy wells around Nb atoms, causing hydrogen to form cage-like diffusion pathways centered on Nb atoms, which effectively restricts long-range hydrogen diffusion in <i>γ</i>-U. Although Nb’s hydrogen trapping ability decreases at higher hydrogen concentrations, it still plays a crucial role in preventing the nucleation of UH₃. Based on these findings, we propose a strategy for predicting hydrogen diffusion kinetics in a series of U-X (X = Ti, Tc, Nb, Mo, Re, Zr, In, Tl) alloys using first-principles static calculations, and establish a near-linear correlation between diffusion energy barriers, X-H bond lengths, and alloy formation energies. Our study underscores the importance of first-principles calculations in selecting suitable alloying elements to regulate hydrogen diffusion in uranium alloys, offering valuable insights with significant implications for engineering applications.</p>