Abstract: The flotation separation of Cu–Fe sulfide minerals at low alkalinity can be achieved using selective depressants. In the flotation system of Cu–Fe sulfide minerals, depressants usually preferentially interact with the pyrite surface to render the mineral surface hydrophilic and hinder the adsorption of the collector. This review summarizes the advances in depressants for the flotation separation of Cu–Fe sulfide minerals at low alkalinity. These advances include use of inorganic depressants (oxidants and sulfur–oxygen compounds), natural polysaccharides (starch, dextrin, konjac glucomannan, and galactomannan), modified polymers (carboxymethyl cellulose, polyacrylamide, lignosulfonate, and tricarboxylate sodium starch), organic acids (polyglutamic acid, sodium humate, tannic acid, pyrogallic acid, salicylic acid, and lactic acid), sodium dimethyl dithiocarbamate, and diethylenetriamine. The potential application of specific inorganic and organic depressants in the flotation separation of Cu–Fe sulfide minerals at low alkalinity is reviewed. The advances in the use of organic depressants with respect to the flotation separation of Cu–Fe sulfide minerals are comprehensively detailed. Additionally, the depression performances and mechanisms of different types of organic depressants on mineral surfaces are summarized. Finally, several perspectives on depressants vis-à-vis flotation separation of Cu–Fe sulfide minerals at low alkalinity are proposed.