This review summarizes the key points and focuses on the use of green solvents in reversed-phase high-performance liquid chromatography. Ethanol, acetone, ethyl lactate, propylene carbonate, dimethyl carbonate, methyl acetate, Cyrene, and glycerol are examined as green solvents, with an emphasis on their properties related to HPLC applications. A total of 135 articles published between 1990 and the present, which utilize ethanol-water mobile phases in RP-HPLC, highlight the established use of ethanol as a green solvent for RP-HPLC. Although ethanol is often characterized by its high viscosity and UV absorbance, it remains one of the most commonly used green solvents. This study shows that approximately 30% of the ethanol-based methods developed employed columns with reduced particle diameters, without the need for column heating. In 26% of cases, UV detection was used, even at wavelengths egal to or below 220 nm. However, ethanol's volatility and flammability pose risks of operator exposure and fire hazards. Consequently, alternative solvents have been explored to mitigate these issues. Acetone, with over 20 years of use, presents similar safety concerns, compounded by its high UV absorbance. Recent advances in greener solvents, such as Cyrene, glycerol, and natural deep eutectic solvents, have been investigated to address VOC concerns in HPLC. However, these solvents still face challenges, including UV absorption, immiscibility with water, high viscosity, and limited availability in HPLC-grade quality. Therefore, additional research is needed to facilitate their broader application.Read less <