Red-bed mudstone is widely distributed in China. The subgrade fillers of weathered red-bed mudstone are easy to cause engineering disasters such as disintegration and deformation under the change of humidity. Therefore, it is necessary to modify the water resistance of coarse granular fillers and improve their disintegration resistance. The red-bed mudstone was modified with octadecylamine to reduce its surface wettability and surface free energy. The hydrophobic properties of the modified soil were characterized by contact angle test and capillary water absorption test, and the optimal ratio of octadecylamine was obtained. The mechanism of hydrophobicity was analyzed by electron microscopy (SEM), infrared spectroscopy (FTIR) and X-ray diffraction (XRD). It was found that the polar molecules of octachylamine entered into the clay mineral layers to form tightly packed compounds based on ion–dipole intercalation, which improved the hydrophobicity of red-bed mudstone. The research can provide reference for prevention of red-bed mudstone subgrade disintegration disease in the future.