To study the effect of post-grouting on the mechanical properties of the interface between soil and structure, a total of 22 groups of direct shear tests were conducted on samples with post-grouting sand-concrete interface under three grouting pressures, three grouting volumes, and four loading conditions. The influence of grouting conditions and loading conditions on the mechanical properties, shear dilation, and strength parameters of the sand-concrete interface were analyzed by using self-developed grouting equipment and grouting method. Test results show that the interface peak shear stress increased with the increase of grouting volume when the grouting pressure and normal stress remained unchanged. When the normal stress of the interface increased, the improvement effect of the grouting on the mechanical properties of the interface gradually decreased with the increase of the grouting volume. When the grouting pressure was low, the change of the interface peak shear stress was not obvious with the grouting volume and normal stress remained unchanged. When the grouting pressure reached a certain value, the increase of the interface peak shear stress was obvious. The shear strength enhancement coefficient of the interface was between 1.1 and 2.0 under different grouting and loading conditions. The shear behavior of the post-grouting sand-concrete interface was mainly improved by increasing the equivalent cohesion of the interface. The equivalent internal friction angle was approximately the same as that of the non-grouting interface. The shear contraction of the interface occurred under non-grouting conditions, and the maximum value of shear contraction increased with the increase of normal stress. Post-grouting could change the interface shear dilation mode for low normal stress. Under the same normal stress, with the increase of grouting volume and grouting pressure, the maximum value of shear dilation increased whereas the maximum value of shear contraction decreased.