Abstract: Depressants are crucial for the selective separation of mineral flotation. Depressants can be classified into organic and inorganic depressants. Inorganic depressants have the disadvantages of toxicity, large dosage, and poor separation efficiency. Therefore, organic depressants are more suitable for mineral separation due to their advantages of biodegradability, comprehensive source, environmentally friendly, and high selectivity. Carboxymethyl cellulose (CMC) is an efficient, nontoxic, and biodegradable mineral-processing depressant widely used in the selective flotation of typical sulfide ores. CMC is one of the essential reagents for cyanide-free and dichromate-free flotation. Therefore, applying and promoting the use of CMC has positive practical significance environmentally. Although research on applying CMC in mineral processing has been conducted in the past, the depression effect of CMC on sulfide ore flotation and its influencing factors have not been systematically summarized. Many sulfide ores frequently coexist with magnesium-containing silicate minerals, such as talc. Adding CMC has a depression effect on sulfide ore and gangue minerals, such as talc. This paper reviews the depression mechanism of CMC on typical sulfide ores, such as galena, chalcopyrite, and pyrite. The results show that the depression effect of CMC on typical sulfide ores is primarily related to the carboxyl and hydroxyl groups in CMC. Both groups depress the typical sulfide ore through hydrogen bonding, electrostatic interaction, and chemical action on the mineral surface. There is a view that the depression of CMC on pyrite relates to its supramolecular conformation. Furthermore, this paper summarizes the depression mechanism of CMC on magnesium-containing silicate gangue. Magnesium silicate gangue, represented by talc, easily clots during grinding, increasing the beneficiation challenges. By adding CMC, the surface wettability can be adjusted and, thus, depress gangue. Finally, this paper systematically expounds on the influence of CMC’s properties, pulp pH, presence of other metal ions, reagent dosage, reagent addition order, and other factors on CMC depression performance in sulfide ore flotation. The summary of the depression effect and influencing factors of CMC can guide and provide a reference for improving the selectivity of reagents and developing new high-efficiency organic depressants. It is of great practical significance to realize the efficient separation of valuable and gangue minerals in sulfide ore flotation.