To achieve the efficient flotation desilication of magnesite tailings (MT), this research systematically investigated the selective adsorption behavior of dodecylamine (DDA) and its compound collectors formed by mixing with Polysorbate surfactants and DDA. The investigation integrated experimental and simulation approaches. The results of the flotation experiment showed that the compound collector improved the MgO grade of the concentrate by 0.20% compared to DDA alone. Additionally, the SiO2 content was reduced by 1.04%, and the concentrate achieved a MgO grade of 41.95%. Molecular simulations provided new insights into the enhanced flotation mechanism with compound collectors, focusing on the size effect of collectors at the solid/liquid interface and bubble modification of collectors at the gas/liquid interface. The analysis indicates that small-size compound collectors can optimally utilise the collecting performance of individual DDA molecules, thereby effectively reducing reagent consumption per unit. Correlation tests indicate a notable enhancement in the hydrophobicity of the quartz surface subsequent to the application of the compound collector, suggesting that the compound collector exhibits a more solidophilic characteristic than DDA. The collectors of the compound facilitate the movement of water molecules on the bubble surface. This leads to a significant increase in the hydrophobicity of the bubble surface, which in turn increases the likelihood of bubble-particle contact collision and adhesion. Compared to DDA, the low dosage of compound collector has the potential to reduce costs and lay the foundation for industrial-grade MT flotation purification.