This work reports on a rapid and sensitive analytical method intended to be used for investigation of 25 multiclass pharmaceuticals in sediments. The method comprises a modified quick, easy, cheap, effective, rugged and safe (QuEChERS) extraction, followed by ultra-high-performance liquid chromatography–high-resolution linear ion trap/Orbitrap mass spectrometry, operated in positive ionization mode. The crucial parameters of both extraction and cleanup as well as those related to liquid chromatography and mass spectrometry were optimized and the method was validated in terms of accuracy, method detection and quantification limits, precision, linearity, and matrix effects. A matrix-matched calibration approach and isotopically labeled internal standards were employed for quantification and correction of matrix effects. In the optimized method, recoveries were calculated to be between 64 and 101% in the intermediate spiking level, with a relative standard deviation below 14%. Method quantification limits ranged from 1.3 to 47 ng g−1. The linearity, expressed as a correlation coefficient, was over 0.998 in all cases, within a range from each compound’s method quantification limit to 250 ng g−1. The matrix effect study revealed slight signal suppression that decreased after the cleanup step for 50% of the pharmaceuticals, proving its adequacy to limit matrix interferences, without causing any important loss of relevant analytes. The applicability of the method was successfully tested in sediments from two Greek rivers in northwestern Greece, revealing the presence of paracetamol, risperidone, venlafaxine, citalopram, and carbamazepine and estimating for the first time the potential occurrence of pharmaceuticals in these two aquatic systems.