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Cytotoxicity is a critical property in determining the fate of a small molecule in the drug discovery pipeline. Cytotoxic compounds are identified and triaged in both target-based and cell-based phenotypic approaches due to their off-target toxicity or on-target and on-mechanism toxicity for oncology and neurodegenerative targets. It is critical that chemical-induced cytotoxicity be reliably predicted before drug candidates advance to the late stage of development, or more ideally, before compounds are synthesized. In this study, we assessed the cell-based cytotoxicity of nearly 10,000 compounds in NCATS annotated libraries against four 'normal' cell lines (HEK 293, NIH 3T3, CRL-7250 and HaCat) using CellTiter-Glo (CTG) technology and constructed highly predictive models to estimate cytotoxicity from chemical structures. There are 5,241 non-redundant compounds having unambiguous activities in the four different cell lines, among which 11.8% compounds exhibited cytotoxicity in two or more cell lines and are thus labelled cytotoxic. The support vector classification (SVC) models trained with 80% randomly selected molecules achieved the area under the receiver operating characteristic curve (AUC-ROC) of 0.88 on average for the remaining 20% compounds in the test sets in 10 repeating experiments. Application of under-sampling rebalancing method further improved the averaged AUC-ROC to 0.90. Analysis of structural features shared by cytotoxic compounds may offer medicinal chemists heuristic design ideas to eliminate undesirable cytotoxicity. The profiling of cytotoxicity of drug-like molecules with annotated primary mechanism of action (MOA) will inform on the roles played by different targets or pathways in cellular viability. The predictive models for cytotoxicity (accessible at https://tripod.nih.gov/web_adme/cytotox.html) provide the scientific community a fast yet reliable way to prioritize molecules with little or no cytotoxicity for downstream development.