In this study, chitosan-grafted-polyacrylamide (Chi-g-PAM), a synthetic biocompatible polymer was investigated as a selective depressant of iron sulfide minerals [i.e., pyrite (FeS2)] in the flotation process of base metal sulfide minerals [i.e., galena (PbS), chalcopyrite (CuFeS2), and sphalerite (ZnS)]. Chi-g-PAM was successfully synthesized by grafting polyacrylamide chains onto chitosan backbone. The synthesized polymer was characterized using Attenuated Total Reflectance-Fourier Transform Infrared Spectroscopy (ATR-FTIR), Nuclear Magnetic Resonance (NMR), Scanning Electron Microscopy (SEM), and X-ray Powder Diffraction (XRD) analysis. Adsorption studies of Chi-g-PAM on mineral surfaces were conducted using zeta potential, contact angle, and total organic carbon (TOC) measurements in addition to X-ray Photoelectron Spectroscopy (XPS). Adsorption tests showed that Chi-g-PAM was most selective to pyrite as compared to the base metal sulfides indicating that this polymer may have the potential to be used as pyrite's depressant in the flotation of base metal sulfides under specific conditions. XPS studies suggested that the depression of pyrite by Chi-g-PAM was due to chemisorption of the amine, amide, and hydroxyl groups of Chi-g-PAM at pyrite-water interface. The impact of Chi-g-PAM on the flotation response of sulfide minerals was investigated in both microflotation and batch flotation systems using model minerals and real sulfide ore, respectively. In microflotation tests of model minerals, the best separation efficiencies between valuable base metal sulfides and pyrite were achieved at pH 7. In batch flotation tests of complex sulfide ore of Mississippi Valley type (MVT) at natural pH (7.8), a separation efficiency of 61% was achieved between galena and pyrite when Chi-g-PAM was used compared to 35% with sodium cyanide (NaCN), the depressant that is commonly applied for this type of ore. However, the separation efficiency between chalcopyrite and pyrite was 15% and 21% with Chi-g-PAM and NaCN, respectively. Comparative studies indicated that Chi-g-PAM outperformed other depressants at producing less pyrite-diluted flotation concentrates.