<p>Silver is a crucial rare and valuable metal in industrial applications, primarily found in polymetallic sulfide deposits as sulfides. The adsorption compatibility between various types of associated silver ores and collectors has not been extensively studied. This research focuses on acanthite (Ag₂S), the predominant mineral in such ores. The study systematically investigates the adsorption compatibility differences between dithiophosphate collectors with five distinct substituents and associated silver ores. This investigation combines computational chemistry simulations with experimental validations. The findings reveal that the −N₂PS₂⁻-type collector exhibits superior surface matching with acanthite (100) surface compared to the −O₂PS₂⁻-type collector. Moreover, the presence of −C−O−C− bonds and benzene rings enhances the effectiveness of dithiophosphate-type collectors for acanthite. In contrast, the compatibility of the −C₂PS₂⁻-type 3418A collector, lacking characteristic groups, is relatively poor. In high-alkali processes, the adsorption of Ca(OH)⁺ hinders the reactivity of silver atoms with the collector. The presence of benzene rings and −NH− groups in the substituents intensifies the impact of Ca(OH)⁺ on the collector, thereby diminishing its adsorption strength. The introduction of −C−O−C− does not modify the sensitivity of the −O₂PS₂⁻-type collector to Ca(OH)⁺. Furthermore, the adsorption of alkane −C₂PS₂⁻-type collectors on mineral surfaces remains unaffected by the attenuating effect of Ca(OH)⁺. The results of the flotation tests, Zeta potential, and adsorption capacity assessments further validated the conclusions derived from computational chemistry analyses. The results provide valuable insights for the future design and advancement of innovative collectors customized for silver ore applications.</p>