A simple, specific, and rapid analytical method for the determination of trimethoprim (TMP) and three sulfonamide (SA) antimicrobial drug residues in buffalo meat is developed and validated. This method is based on a solid-phase extraction technique followed by high-performance liquid chromatography (HPLC)–photodiode array (PDA) detection. Target compounds were extracted from the meat by acetonitrile and water, cleaned up on a Bond Elute C₁₈ cartridge column, and separated on a RP-C₁₈ column during HPLC analysis. Acetonitrile along with water appears to be an excellent extractant as recovery of the analytes at maximum residues levels (MRLs) in spiked sample was in the range of 75–108%, with coefficient of variations (CVs) ranging between 1.34 and 22%. The limit of detection (LOD) and the limit of quantification (LOQ) were 0.031 and 0.062 µg/g, respectively, for all of the compounds. Intra- and interday assay precisions of the method at 0.125 µg/g concentrations for any drug ranged between 3 and 4%. The linearities of the TMP, sulfadimidine (SDM), sulfadoxine (SDO), and sulfamethoxazole (SMX) were 0.9989, 0.9999, 0.9998, and 0.9997, respectively. For robustness, the analytical method was applied to 122 buffalo meat samples obtained from export meat processing plants.