Phosphogypsum (PG), a by-product of wet-process phosphoric acid production, holds significant potential for use in construction and other industrial applications. However, impurities such as quartz, while not posing direct environmental hazards, negatively impact critical properties like whiteness, limiting PG’s practical utility. Addressing these impurities is therefore essential to enhance PG’s performance and expand its applicability. In this study, the selective separation of quartz from gypsum (CaSO4·2H2O) was investigated using tetradecyl trimethyl ammonium chloride (TTAC) as a novel cationic collector. Microflotation experiments were conducted over a broad pH range (2.5–9.5) to evaluate the separation efficiency. TTAC demonstrated excellent selectivity for quartz, achieving its peak performance at neutral pH. The peak recovery of 96 % (vs. 21.5 % for gypsum) at neutral pH (7.0 ± 0.1) with a low TTAC concentration of 100 mg/L. Adsorption tests revealed a maximum adsorption capacity of 12.8 mg/g on quartz, while contact angle measurements showed a 143 % increase in hydrophobicity (from 28.4° to 69.1°). Mechanistic analyses via zeta potential, FT-IR, and XPS confirmed electrostatic interactions and hydrogen bonding as dominant adsorption mechanisms. These analyses revealed that TTAC selectively interacts with quartz through electrostatic interactions and hydrogen bonding, while its weaker interaction with gypsum is driven primarily by minimal electrostatic forces. The findings establish TTAC as an effective reagent for improving the purity of PG. This enhanced purity not only increases PG’s suitability for large-scale industrial applications but also addresses significant environmental challenges with PG waste, paving the way for its sustainable utilization.