Whilst many efforts have been well documented on the readily available flotation surfactants, more kinds of newly-designed surfactants and auxiliary reagents for froth flotation process are still highly demanding. Herein we report the facile fabrication of a series of polyhedral oligomeric silsesquioxanes (POSS)-based froth flotation giant surfactants via two-step sequentially performed thiol-ene "click" reactions, with precisely-controlled chemical structures and tunable multisite surface functionality. The resulting giant surfactants performed high mineral recovery efficiency in the flotation testing of quartz, hematite and apatite in a broad range of pH conditions. We describe these POSS-based surfactant molecules in an initial proof-of-concept study and propose that this class of giant amphiphiles will be useful in flotation separation technique.