The mechanical properties of the soil-structure interface have always been one of the key and hot issues in the field of geotechnical engineering, and revealing its mechanism is helpful to promote the understanding of the bearing characteristic of structures such as pile foundations and retaining walls. A total of 28 groups of large direct shear tests with the post-grouting sand–concrete interface were conducted under three different grout volumes and four kinds of loading and unloading conditions to analyze the interface mechanical properties and the distribution of shearing influence range. The test results show that grouting can gradually eliminate the difference between the interface’s initial shear modulus and shear stress due to the loading and unloading of the interface. The softening phenomenon doesn’t exist in the un-grouted interface, while the post-grouting interface exhibits softening and the softening occurs in the unloading interface shearing process with low applied normal stress. The grout cement improves the mechanical properties of the interface by increasing the equivalent cohesive force of the interface but has no significant effect on the equivalent internal friction angle of the interface. The improvement of the interface equivalent cohesive force on the loading interface is better than the unloading interface under the same grout volume. The distribution of interface shearing influence range under unloading conditions is slightly larger than that under the loading conditions. Regardless of the loading, unloading, and grouting conditions, the distribution of interface shearing influence range is positively correlated with the interface peak shear stress. Under the same applied normal stress, the mechanical properties of the unloading post-grouting interface were improved due to the formation of the grout bulb by compaction grouting to increase the roughness of the concrete plate, while the mechanical properties of the loading post-grouting interface were improved by penetration grouting to form the soil-cement mixture. The research results can provide guidance for the post-grouting of pile foundations in practical projects.