In this paper, a novel macromolecular depressant polymaleamide-propyl dithiocarbamate (PMA-PDTC) was designed and synthesized according to density functional theory (DFT) calculations results, and its structure was characterized by infrared spectra (IR). The flotation experiments results demonstrated that PMA-PDTC was an effective depressant for galena in separating galena from chalcopyrite, and it exhibited a stronger depressing ability and a better selectivity for galena than for chalcopyrite. When the dosage of PMA-PDTC was 2.0 mg/L, a good separation result was obtained with O-isopropyl-N-ethyl thionocarbamate (IPETC) as collector at pH 8.5 for an artificial mixture of Cu-Pb minerals. The Cu concentrate could reach a grade of 28.89% containing 12.12% Pb, and the Pb concentrate could reach a grade of 80.65% containing 1.49% Cu. The experimental results agreed with the DFT calculations results well, which indicated that DFT method was useful for predicting the adsorption strength of some molecules on mineral surfaces and for guiding the design of the depressant for galena or other minerals.