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An access to fast and non-invasive techniques to infer or predict the drug-induced injury caused by newly developed drugs and to monitor therapeutic efficacy of established drugs during treatment are of the outmost importance in pharmaceutical industry and clinical diagnosis. Peptidome and low molecular weight proteome profiling is an emerging technique that allows the recognition of distinctive patterns and differentiation among diverse physiopathological conditions. In this article, we evaluated the utility of peptide/small protein profiling using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) coupled with WCX magnetic bead-based solid-phase extraction as a screening tool for drug toxicity assessment in urine samples. Given that drug-induced injury is primarily reflected in liver, three different, well-described hepatotoxic drugs were chosen for this work. These were: carbon tetrachloride (CCl(4)) which induces liver fibrosis, D(+)-galactosamine as a model for acute liver injury, and Escherichia coli-derived lipopolysaccharide to study the damage caused by endotoxins. The profiles obtained with a correct clustering analysis show that this methodology can be used as a non-invasive and straightforward approach to test for potential drug toxicity. Pharmaceutical research and drug development studies could benefit from this methodology as liver injury inducer compounds could be easily detected in vivo by non-invasive means, accelerating the launch of safer drugs to the market.