How to realize efficient treatment of coal slime generated by a coal washing operation is an urgent problem to be solved in this industry. The presence of clay minerals, especially highly hydrophilic montmorillonite (MMT), is the key to the poor treatment effect of coal slime. Polyacrylamide (PAM) is very popular as a polymer agent to improve the treatment of coal slime. However, when it is used to treat coal slime with a high content of MMT, the selection of PAM type and the mechanism of action are still lacking. In this study, the effects of different types of PAM on the treatment of coal slime water containing MMT are considered by sedimentation and press filtration tests. The interaction mechanism of PAM on the MMT surface is studied by using ζ-potential, Brunauer-Emmett-Teller (BET) analysis, low-field nuclear magnetic resonance, density functional theory (DFT), and molecular dynamics (MD) simulations. The results show that the three PAM can improve the sedimentation and filtration effect of coal slime water, and the performance is CPAM > NPAM > APAM. The ζ-potential of the MMT (001) surface increases under the action of three PAM, and the effect of CPAM is the most significant. The adsorption of PAM on the MMT (001) surface has the ability to neutralize the surface charge of MMT. The flocculation of MMT particles under PAM results in an increase of particle size and a decrease of specific surface area. Meanwhile, the pore volume of MMT decreases, and the average pore size increases. In addition, PAM mainly removes vicinal water on the MMT surface. The active sites of the MMT surface and PAM are calculated by DFT. The adsorption of three PAM structural units on the MMT Na-001 surface and non-001 surface is nonbonding interaction, and the adsorption energy of CPAM is the largest. And the left shift of εp of the O atom on the MMT surface is conducive to the stable adsorption of CPAM. The MD results show that the concentration of water molecules on the surface of MMT Na-001 decreases after PAM is adsorbed on the MMT Na-001 surface, indicating that PAM can keep water molecules away from the surface of MMT, which means that the hydrophobicity of the MMT surface is enhanced. This study has guiding significance for the selection of PAM and the development of new flocculants in the treatment of coal slime with a high content of MMT.