A simple, cost effective, and efficient dispersive liquid–liquid microextraction (DLLME) method was developed and optimized for the determination of mifepristone, benzophenone, eicosapentaenoic acid, and docosahexaenoic acid in different environmental water matrices followed by UHPLC–QTOF–MS analysis. In the preliminary experiments, the univariate optimization approach was used to select tetrachloroethylene and acetonitrile as extraction and disperser solvents, respectively. The significant factors influencing DLLME were screened using full factorial design, and the optimal values for each variable were then derived through further optimization using central composite design with desirability function. The optimal conditions were achieved with 195 µL of tetrachloroethylene as extraction solvent, 1439 µL of acetonitrile as disperser solvent, and sample pH of 5.8. Under these conditions, the method provided the detection limits ranging from 0.11–0.48 µg/L and recoveries ranging from 23.32–145.43% across all samples. The enrichment factor obtained ranged from 11.66–72.72. The proposed method was then successfully applied in wastewater treatment plant influent and effluent, including river water receiving wastewater treatment plant effluent discharge. Only benzophenone was detected in the concentration range of 0.79–0.88 µg/L across all the water samples. The calculated risk quotient resulting from benzophenone exposure in water samples showed a low potential risk to human health and the aquatic ecosystem. The method was also evaluated for its environmental friendliness using various metrics tools such as Analytical Eco–Scale (AES), Green Analytical Procedure Index (GAPI), Analytical GREEnness (AGREE), Analytical Greenness for Sample Preparation (AGREEprep), and Sample Preparation Metric of Sustainability (SPMS). Only AES qualified the method as green while it was considered acceptable and sustainable when assessed using SPMS.