A multiresidue method was developed and validated for the determination of 13 neonicotinoid pesticides and metabolites, and nine macrocyclic lactone pesticides and veterinary drugs using SPE and ultra-performance liquid chromatography/MS/MS. The method was validated in milk, orange, spinach, apple, plum, watermelon, green bean, zucchini, broccoli, strawberry, grape, and tomato by analyzing replicates of residue-free control samples fortified with a mixture of 22 target analytes at three concentration levels. The recoveries of the analytes from the fortified matrixes were mostly within 70-120%, except for some of the neonicotinoid metabolites. The LOD values varied by analyte and matrix and ranged between 0.001-2 ng/g. The developed method was successful in combining two widely different classes of compounds into a single analysis.