UltraPerformance convergence chromatography (UPC²™) is a new category of separation science which utilizes the unrealized potential of the supercritical chromatography phenomenon. UPC²™ is a stand-alone, viable technique that is cost effective, sustainable, and uses green technology that lowers the use of organic solvents. Based on this advantage, we explored a simple and robust supercritical liquid-based UPC² method in order to increase sample throughput and productivity to quantify the diastereomers of fulvestrant. The two isomers of fulvestrant were well separated on a chiral column (150 mm × 4.6 mm, I.D.) by applying a mixture of methanol and acetonitrile (9.5 : 0.5) as the co-solvent of the mobile phase of carbon dioxide (75%). The detection was carried out at 280 nm. We were able to achieve a three-fold reduction in retention with an isocratic mode as compared to the United States Pharmacopoeias (USP) normal phase method. This new method was validated in accordance with the ICH guidelines; it exhibited good intra- and inter-day accuracy, precision, and the results were linear over a range of 25% to 150% of the target concentration. The method could be successfully applied for the determination of the diastereomeric ratio of fulvestrant as an API and in fulvestrant injectable finished products.