Abstract: Uranium-based metallic fuels show great potential for advanced fast reactors due to high thermal conductivity and energy density. However, α-U suffers from poor structural stability and strong elastic anisotropy at low-temperature, which severely affect its processability and irradiation performance (for instance irradiation swelling and growth). Alloying with transition metals (Ti, Zr, Nb, and Mo) is a common strategy to increase its melting point and optimize its properties. On the other hand, lanthanide and actinide products (Ce, Nd, Pu, and Am) can be introduced under service conditions. These alloy elements can affect fuel processing properties and in-pile irradiation behavior, such as irradiation growth and swelling, and this is strongly correlated with the elastic constants and anisotropy of α-U. Therefore, the effects of alloy elements on the elastic constants and anisotropy of α-U were investigated to provide fundamental mechanical parameters for integrated fast reactor fuel design. The first-principles thinking calculations based on density functional theory (DFT) with the GGA-PBE functional were performed using the VASP code. Orthorhombic α-U supercells (1×1×1, 2×1×1, 2×2×2) were built to model the different doping concentrations, including 25%, 12.5%, and 3.125%. The elastic matrices were obtained via energy-strain relationships, and bulk, shear and Young’s moduli were derived using the Voigt-Reuss-Hill model. The universal anisotropy index (A^U) and normalized standard deviation method were used to quantitatively evaluate the anisotropy, and the electronic origins of the mechanical properties could be obtained by density of states (DOS) analyses. The calculated results show that transition metal generally reduces the elastic constants and moduli of α-U, and only Am significantly lowers the moduli while Ce, Nd and Pu have minor effects for lanthanide/actinide elements. The strong anisotropy of α-U originates from the puckered (010) planes, and most dopants cannot significantly mitigate this feature, for instance, Nb reduces anisotropy, whereas Zr and Am notably enhance it. DOS analyses indicate transition metals disrupt Fermi-level 5f-6d hybridization and the pseudo-gap, weakening bonding and reducing moduli. Am strengthens f-d hybridization without destroying the pseudo-gap, also lowering moduli. With increasing doping concentration, Young’s and shear moduli decrease overall, while bulk modulus rises locally at 12.5% for Nd, Zr, Mo and Am. This may be due to the local atom arrangement environment. This work clarifies alloying effects on α-U’s elasticity and anisotropy at the electronic level. It confirms Nb as an effective additive to reduce anisotropy, while Zr and Am exacerbate it. The findings offer reliable mechanical data for advanced metallic fuel development and guide performance optimization of α-U-based alloys.