Ultrasound-assisted matrix solid-phase dispersion (MSPD) was applied to isolate eight cephalosporins (cefadroxil, cefaclor, cephalexin, cefotaxime, cefazolin, cefuroxime, cefoperazone and ceftiofur) from milk. Multi-residue analysis was subsequently performed by HPLC-diode array detection. Extraction yield by matrix solid-phase dispersion using Nexus sorbent was higher than various investigated SPE protocols. Three analytical columns, two conventional silica based and one monolithic, were compared based on resolution, peak shape and retention time. The optimum method using Chromolith RP-18e (100×4.6 mm) achieved separation in less than 16 min. Method validation was performed according to the European Union Decision 2002/657/EC, determining linearity, selectivity, stability, decision limit, detection capability, accuracy and precision. RSD values observed were lower than 15.3%. Recovery rates of examined antimicrobials from milk ranged from 93.8 to 101.9% for cefadroxil, from 94.7 to 103.6% for cefaclor, from 93.4 to 106.6% for cephalexine, from 104.1 to 115.3% for cefotaxime, from 97.1 to 105.6% for cefazolin, from 97.4 to 108.6% for cefuroxime, from 98.8 to 103.4% for cefoperazone and from 95.5 to 103.6% for ceftiofur. Correlation coefficients ranged from 0.9926 to 0.9999. CC(b) values were in the range from 103.5 to 112.3 μg/kg for analytes with a maximum residue limit of 100 μg/kg and from 54.4 to 56.3 μg/kg for those with a maximum residue limit of 50 μg/kg.