The collecting performance of four typical sulfide collectors—sodium butyl xanthate (SBX), ammonium dibutyl dithiophosphate (ADD), sodium diethyl dithiocarbamate (DDTC), and O‑isopropyl‑N‑ethyl thionocarbamate (Z‑200) - with acanthite (Ag2S) was investigated using DFT calculations, frontier orbital analysis, and flotation tests. Frontier orbital matching and energy difference calculations reveal that ADD forms a σ‑bond with the LUMO of three‑coordinated Ag and a back‑donating π‑bond with the HOMO of four‑coordinated Ag on acanthite. ADD exhibits the smallest HOMO–LUMO energy gap with acanthite (ΔE₁ = 0.1438 eV) and weaker adsorption energies toward Zn²⁺ and Fe²⁺ than SBX and DDTC. Single‑mineral flotation confirmed that ADD achieves the highest acanthite recovery (~85%), while mixed‑mineral flotation showed that ADD significantly improves silver grade (19.56% vs. 16.08%) and recovery (85.91% vs. 73.30%) compared to SBX, while effectively depressing sphalerite (Zn recovery 31.79% vs. 69.14%). Combined theoretical and experimental results demonstrate that ADD exhibits both strong collecting ability and high selectivity, making it a promising collector for associated silver sulfide ores. The frontier orbital‑based screening approach provides a theoretical foundation for designing specialized collectors for silver minerals.