The effects of Fe doping and applied hydrostatic pressure on structural, mechanical and electronic properties of Zr8Cu8-xFex (x = 0, 1, 2, 3) are investigated via the first-principles calculations. The equation of state (EOS) is established for B2–CuZr crystalline structure. The values are in good agreement with previous experimental results. The phase stability is improved simultaneously by the substitution of Fe for Cu and enhanced hydrostatic pressure for Zr8Cu8-xFex (x = 0, 1, 2, 3). Doping concentration plays an important role in tuning the values of bulk modulus B. However, the values of Vickers hardness HV follows the sequence as: Zr8Cu6Fe2 > Zr8Cu7Fe1 > Zr8Cu5Fe3 > Zr8Cu8 (0–30 GPa). The sequence of B/G, Poisson's ratio ʋ is just opposite to that of HV. It implies a strong correlation between ductility and charge density topology (closely related to bonding character and substitutional atomic sites). Substitution of Fe for Cu tailor the metallic characteristic of Zr–Cu bond into more directional covalent characteristic of Zr–Fe bond, thus make doped Zr8Cu8-xFex (x = 1, 2, 3) harder and more brittle than non-doped Zr8Cu8. The hydrostatic pressure generally enhances the predominant metallic character of Zr8Cu8-xFex (x = 0, 1, 2, 3), thus make all doped and non-doped compositions transit into a more ductile regime. The combined effects of directional bonding and pressurizing thus make Zr8Cu6Fe2 (0 GPa) the most hard and brittle material and Zr8Cu8 (30 GPa) the most ductile material among all compositions.