Off-target drug interactions are a major reason for candidate failure in the drug discovery process. Anticipating potential drug’s adverse effects in the early stages is necessary to minimize health risks to patients, animal testing, and economical costs. With the constantly increasing size of virtual screening libraries, AI-driven methods can be exploited as first-tier screening tools to provide liability estimation for drug candidates. In this work we present ProfhEX, an AI-driven suite of 46 OECD-compliant machine learning models that can profile small molecules on 7 relevant liability groups: cardiovascular, central nervous system, gastrointestinal, endocrine, renal, pulmonary and immune system toxicities. Experimental affinity data was collected from public and commercial data sources. The entire chemical space comprised 289′202 activity data for a total of 210′116 unique compounds, spanning over 46 targets with dataset sizes ranging from 819 to 18896. Gradient boosting and random forest algorithms were initially employed and ensembled for the selection of a champion model. Models were validated according to the OECD principles, including robust internal (cross validation, bootstrap, y-scrambling) and external validation. Champion models achieved an average Pearson correlation coefficient of 0.84 (SD of 0.05), an R2determination coefficient of 0.68 (SD = 0.1) and a root mean squared error of 0.69 (SD of 0.08). All liability groups showed good hit-detection power with an average enrichment factor at 5% of 13.1 (SD of 4.5) and AUC of 0.92 (SD of 0.05). Benchmarking against already existing tools demonstrated the predictive power of ProfhEX models for large-scale liability profiling. This platform will be further expanded with the inclusion of new targets and through complementary modelling approaches, such as structure and pharmacophore-based models. ProfhEX is freely accessible at the following address:https://profhex.exscalate.eu/.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13321-023-00728-6.