Objective The effect of sciatic neurectomy (SN) on the meso-mechanical properties of cortical bone was explored by combining animal modeling and resonant ultrasound spectroscopy. Methods A total of five New Zealand White rabbits underwent unilateral SN and cortical bone specimens were obtained from the tibias on the operated and normal sides at 4 weeks post-SN; multiple elastic constants (C11, C12, C13, C33, and C44), engineering mechanical parameters, and anisotropy ratios of the bone specimens were acquired using irregular resonant ultrasound spectroscopy under assumptions of transverse anisotropy and the paired t-test was used to assess the differences in the mechanical properties of cortical bone between the two sides. Results Compared with the normal side, the elastic constants in different directions (C11, C12, C13, and C33) of the cortical bone on the operated side showed a decreasing trend, ranging from 8.49% to 32.23%; The axial Young's modulus (E3) and Poisson's ratio (v31) were reduced by 5.85% and 24.07%, respectively, but there was no significant change in the anisotropic properties. Conclusion The method of cortical bone disuse modeling through SN is feasible, which can significantly change the meso-mechanical properties of cortical bone, and the elastic constants can more comprehensively reflect the changes in the mechanical properties of cortical bone.