A comprehensive trace analysis method was developed in this study for the quantification of four commonly used pharmaceuticals, namely diclofenac, cetirizine, triclosan, and phenylephrine, in Winestead drain river water from the Humber Region United Kingdom. The method involved a combination of solid phase extraction (SPE) and liquid chromatography mass spectrometry (LC-MS/MS), offering a sensitive and selective approach for the detection and quantification of these pharmaceutical compounds. The water samples were collected from three different locations along the Winestead drain and subjected to SPE using a suitable sorbent material. The analytes were retained on the sorbent, The interfering matrix components were washed away while the retained analytes were eluted using an appropriate solvent, the eluted samples were then analysed using a high-performance liquid chromatography (HPLC) system coupled with a tandem mass spectrometer. Multiple reaction monitoring (MRM) was used for selective detection and quantification of the pharmaceuticals. The method exhibited excellent linearity over a wide concentration range for all target analytes, with correlation coefficients (R2) ≥0.99, indicating the method's capability to detect these compounds at low concentrations. The precision and accuracy were evaluated by analysing spiked multicomponent solvent, and the results demonstrated satisfactory precision (%RSD < 10%) and accuracy (recovery rates ranging from 55% to 80%). The method developed was applied to analyse river water samples collected from Winestead drain. The presence and concentrations of diclofenac, cetirizine, triclosan, and phenylephrine were determined, highlighting the occurrence of these pharmaceutical compounds in the aquatic environment.