Under the mixed-mode loading condition, mechanical responses of the Al-terminated O-site Ni(111)/α-Al2O3(0001) interface are investigated using first-principle calculations. The displacement-controlled loadings along 22.5, 45, and 67.5° orientations with respect to the interface are applied. The tension and shear responses of the interface are elaborated according to the computational results, including the mechanical strengths, the effect of tension softening, and the failure characteristic. In addition, the stress versus displacement relationships are derived out based on the general approach suggested by [Sun et al., Mater. Sci. Eng., A170, 67 (1993)], and the deviations between the analytical and computational results are examined in particular. Furthermore, the potential function and its development of this interface are discussed in detail.