Due to the scarcity of freshwater, the application of seawater has been considered as an alternative in mineral flotation. Previous studies reported that the challenges of using seawater was due to various ions contained, but not many achievements in relieving their negative effects have been obtained. This study systematically investigated the application of sodium hexametaphosphate (SHMP) in chalcopyrite (CuFeS2) flotation in seawater, as well as in the presence of Mg2+ or Ca2+ (two divalent ions displayed the most significantly negative roles on mineral flotation). It was found that the detrimental effects of seawater on CuFeS2 flotation were primarily due to the formed Mg(OH)2 colloids (major) and CaCO3 precipitates (minor) attaching onto CuFeS2, giving rise to a hydrophilic CuFeS2 surface. The presence of SHMP significantly increased CuFeS2 recovery in seawater and in the solution containing Mg2+ and Ca2+. Two beneficial mechanisms due to SHMP were proposed. Firstly, SHMP combined with Ca2+ and Mg2+ to form dissolvable complexes, reducing the formation of hydrophilic Ca and Mg precipitation. Secondly, SHMP reversed the interaction force between CuFeS2 particles and Mg(OH)2 colloids from attractive to repulsive, thereby reducing the attachment of these precipitates onto CuFeS2 surface. This study therefore provides a promising way in utilizing seawater for mineral flotation.