A method is proposed for determining antihistamines cyproheptadine, diphenhydramine, and tripelennamine in food products and feeds by high-performance liquid chromatography—tandem mass spectrometry. In developing the method, the main aspect was its versatility in terms of the reagents and equipment used to analyze different types of matrices—meat, offal (liver), eggs, milk, honey, butter, and compound feed. A combination of solvents, acetonitrile, water, and hexane (3 mL each), is used to extract the analytes; the sequence of adding solvents depends on the matrix; the remaining stages of sample preparation are standardized. The limits of detection and quantification for antihistamines in the above samples are 0.012–0.3 and 0.04–1 μg/kg, respectively. The relative standard deviation of the analysis results does not exceed 17%. The relative error in determining substances in most cases does not exceed 15%.