A method combining QuEChERS extraction, ultra-high pressure liquid chromatography and full scan high resolution mass spectrometry was evaluated for its use in screening for chemical residues and contaminants in animal-related food matrices. The method was evaluated by analysis of multiple replicates of whole milk, muscle tissue, liver tissue and corn silage. Analytes tested included plant alkaloids, carbamate and organophosphate pesticides, and several types of veterinary drugs. A database containing the chemical formula for each analyte was used to calculate accurate mass-to-charge ratios for expected pseudo-molecular ions. This information, as well as retention times, was used to identify analytes. Of 118 compounds chosen for analysis, 86 were detectable in all fortified replicates of at least one matrix at levels ranging from 1.0 to 5000 ng/g. Variability of response, as measured in % relative standard deviation of peak areas over seven replicate fortified sample analyses, was found to differ among the classes of analytes, ranging from <10% to >100%. Retention times were stable and analytes were routinely detected at measured mass-to-charge ratios within 2 ppm of their theoretical mass-to-charge ratios. These results indicate that the combination of generic extraction and chromatographic procedures with full scan high resolution mass spectrometry can serve as a useful method for screening complex matrices.