The Ames assay is required by the regulatory agencies worldwide to assess the mutagenic potential risk of consumer products. As well as this in vitro assay, in silico approaches have been widely used to predict Ames test results as outlined in the International Council for Harmonization (ICH) guidelines. Building on this in silico approach, here we describe DeepAmes, a high performance and robust model developed with a novel deep learning (DL) approach for potential utility in regulatory science. DeepAmes was developed with a large and consistent Ames dataset (>10,000 compounds) and was compared with other five standard Machine Learning (ML) methods. Using a test set of 1,543 compounds, DeepAmes was the best performer in predicting the outcome of Ames assay. In addition, DeepAmes yielded the best and most stable performance up to when compounds were >30% outside of the applicability domain (AD). Regarding the potential for regulatory application, a revised version of DeepAmes with a much-improved sensitivity of 0.87 from 0.47. In conclusion, DeepAmes provides a DL-powered Ames test predictive model for predicting the results of Ames tests; with its defined AD and clear context of use, DeepAmes has potential for utility in regulatory application.