Current research has trouble explaining the selective flotation mechanism realized by metal ions, which hinders the advancement of effective flotation techniques. In this work, the selective activation flotation of cassiterite from quartz with Pb2+ is taken as an example to illustrate the pivotal roles of surface hydroxyls in selective flotation. Accordingly, flotation, adsorption amount, and X-ray photoelectron spectroscopy (XPS) measurements and systematic first-principles calculations have been used to investigate the roles of hydroxyl groups on the selective adsorption of Pb2+. The obtained flotation, adsorption amount, and XPS test results consistently show that the Pb2+ can more strongly interplay with cassiterite than quartz resulting in selective flotation of cassiterite from quartz. The electron localization functional results illustrate that the electron localization of oxygen of Si-O bonds is stronger than the Sn-O bond resulting in the weaker electron migration ability (high hardness) of oxygen atoms of quartz than oxygen atoms of cassiterite. This makes the cassiterite surface hydroxyl groups less hard than quartz. Further crystal orbital Hamilton population and partial density of states show that the Pb2+ interacts with the oxygen atoms on cassiterite forming chemical bonds before and after the adsorption of benzohydroxamic acid (BHA). On the other hand, the interaction of Pb2+ with quartz is physical in the presence of BHA. The strong adsorption of Pb2+ on cassiterite makes it easier for BHA adsorption which accounts for the selective flotation of cassiterite from quartz. This work sheds new light on establishing a consistent and dependable theory that the hardness of surface hydroxyls is the original factor affecting the selective adsorption of metal ions on oxide mineral surfaces.