The tailing dewatering process meets significant challenges due to the contained clay minerals. The clays often have great hydrophilicity and high electronegativity, which improve slurry stability and prevent particle aggregation. Hydrophobic aggregation of chemical additives such as surfactants is an efficient way to enhance dewatering of clay-rich tailings. This work aims to investigate the interactions between CTAB, a cationic surfactant, and montmorillonite by experiments and molecular simulation. In macroscopic dewatering experiments, the results show that, after the treatment with 0.3 mol/L CTAB, the contact angle of montmorillonite cake and the zeta potential increased from 13.0° to 34.1° and from –21.5 mV to 0.22 mV, respectively. The addition of CTAB resulted in improved clay-rich tailings dewatering due to reduced surface tension of the filtrate, increased particle hydrophobicity, and charge neutralization. Then, the interaction forces between montmorillonite particles at various CTAB concentrations were directly measured. AFM results indicated that the interaction forces between montmorillonite particles in water were always repulsive during the approaching process. As the concentration of CTAB increased, the interaction force changed from repulsive to attractive. The adhesion force between montmorillonites increased to approximately 6.46 nN at 0.3 mmol/L CTAB. These adhesion forces help the montmorillonites readily adhere to each other. Finally, molecular simulation results indicated that the interactions between montmorillonite and water molecules were weakened by CTAB. The thickness of the water film was dramatically reduced by CTAB adsorption, enhancing the hydrophobicity of the montmorillonite surface.