A method employing a type of filtered solid phase extraction based on the PRiME hydrophilic lipophilic balance (HLB) was developed for extracting cephalosporin compounds (cephalexin monohydrate, cefradine, cefazolin, cefotaxime, cefmenoxime, cefoperazone sodium, cefadroxil, cefpirome sulfate, cefquinome sulfate, cefaclor, ceftizoxime, cephalonium, cephalothin sodium, cefamandole lithium, cefathiamidine, cefetamet pivoxyl) from milk samples. Compared to conventional HLB extraction, the PRiME HLB SPE process consists of only one step without activation, elution. It shows the advantage of a faster and better purifying capacity. Ultra-high pressure liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) was used for detection. In order to obtain high recoveries of the analytes, several parameters were optimized, such as variation of the extraction solvents, and the volume of the extraction solvent and dripping washing solution. With an optimized sample preparation, the limit of detection (LOD) and limit of quantification (LOQ) for the multi-reaction-monitoring (MRM) mode of the method varied from 0.02 to 5 μg kg⁻¹, and 0.02 to 10 μg kg⁻¹, respectively. Due to the different sensitivities of the analytes, the calibration curves were linear with R² ≥ 0.991 in their linear ranges. The relative recoveries from the milk samples were between 56% and 93% with relative standard deviations lower than 15%.