Abstract: This study examined the effects of N-bis(phosphonomethyl)glycine (NADMP) on the flotation characteristics of sphalerite and galena using flotation experimentation, contact angle tests, Zeta potential measurements, X-ray photoelectron spectroscopy (XPS), and Density functional theory (DFT), elucidating the selective inhibition mechanism of NADMP towards sphalerite. Results from the flotation tests revealed that the variance in recovery for galena and sphalerite, with a pH setting of 8 and an NADMP concentration of 80 mg/L, surpassed 70%. Surface analysis and simulation results indicated that NADMP chemically adsorbed onto the sphalerite surface by bonding the oxygen atoms in its phosphonic acid functional group’s P-O bond with the zinc atoms of sphalerite. In contrast, its interaction with galena surfaces was relatively weak. The contact angle tests further confirmed the NADMP’s greater impact on the hydrophobicity of the sphalerite surface. Hence, NADMP exhibits selective depressed effects on the sphalerite.