Abstract: In nature, magnesite is frequently intergrown with dolomite and other carbonate minerals, forming complex ores that require efficient separation. The flotation separation of magnesite from dolomite remains a significant challenge in mineral processing owing to their similar crystal structures and solution chemistry, which result in comparable surface hydration properties and flotation behavior. Precise regulation of surface wettability is central to achieving selectivity. Previous research has predominantly focused on developing novel flotation reagents, particularly collectors and depressants, with emphasis on their interaction mechanisms at mineral surfaces. Recent studies employing ab initio molecular dynamics (MD) have provided fundamental insights, indicating that although both minerals favor molecular water adsorption, magnesite exhibits a slightly stronger affinity for water than dolomite, thereby affecting subsequent interfacial processes. Molecular simulation can effectively elucidate such intricate microscopic interactions at mineral–water–collector interfaces. To elucidate the atomic-scale mechanism governing the selective adsorption of collectors, this study integrates density functional theory and MD simulations using Materials Studio software. Structurally optimized surface models of magnesite (104) and dolomite (104), together with a typical anionic collector CP (e.g., a phosphoric acid ester), are constructed to systematically investigate frontier molecular orbital energetics, surface wettability dynamics, and interfacial adsorption energies. Frontier molecular orbital analysis reveals a narrower energy gap between CP and magnesite (2.643 eV) than in the dolomite system (2.670 eV), suggesting that electron transfer from the highest occupied molecular orbital of CP to the LUMO of magnesite is thermodynamically more favorable, thereby promoting selective adsorption on magnesite surfaces. MD simulations of wettability behavior indicate that dolomite exhibits a lower water contact angle (7.5°) than magnesite (9.2°), reflecting its intrinsically stronger hydrophilicity. After CP adsorption, the diffusion coefficient of water molecules on the magnesite surface increases significantly and exceeds that on dolomite, demonstrating that CP adsorption effectively disrupts the hydration layer and enhances the hydrophobicity of magnesite. This enhanced hydrophobicity is expected to facilitate bubble attachment more effectively on magnesite than on dolomite. Interfacial interaction energy analysis further confirms that CP exhibits significantly stronger adsorption energy (−406.8 kJ·mol⁻¹) on magnesite than on dolomite (−95.6 kJ·mol⁻¹), along with higher deformation energy (166.7 kJ·mol⁻¹ vs. 161.9 kJ·mol⁻¹), indicating superior adsorption stability and interfacial compatibility on the magnesite surface. This study elucidates the multidimensional selective mechanism of the CP collector toward magnesite from electronic, dynamic, and energetic perspectives, providing a theoretical foundation for reagent design. To translate these molecular-level insights into practical separation strategies and address the complexity of industrial flotation systems, several aspects warrant further investigation. Future studies should focus on (1) investigating the combined effects of surface pretreatment (e.g., acid etching to modulate roughness and active sites) and CP adsorption; (2) examining the influence of solution chemistry (e.g., dissolved ionic species and pH) on the established adsorption model; and (3) extending simulations to the gas-liquid interface to evaluate the potential role of CP in bubble surface modification and its effect on overall flotation kinetics. These investigations will help bridge the gap between molecular-scale insights and the optimization of macroscopic flotation performance.