Nanoparticles (NPs) have been employed as drug delivery systems (DDSs) for several decades, primarily as passive carriers, with limited selectivity. However, recent publications have shed light on the emerging phenomenon of NPs exhibiting selective cytotoxicity against cancer cell lines, attributable to distinct metabolic disparities between healthy and pathological cells. This study revisits the concept of NPs selective cytotoxicity, and for the first time proposes a high‐throughput in silico screening approach to massive targeted discovery of selectively cytotoxic inorganic NPs. In the first step, this work trains a gradient boosting regression model to predict viability of NP‐treated cell lines. The model achieves mean cross‐validation (CV) Q2 = 0.80 and root mean square error (RMSE) of 13.6. In the second step, this work develops a machine learning (ML) reinforced genetic algorithm (GA), capable of screening >14 900 candidates/min, to identify the best‐performing selectively cytotoxic NPs. As proof‐of‐concept, DDS candidates for the treatment of liver cancer are screened on HepG2 and hepatocytes cell lines resulting in Ag NPs with selective toxicity score of 42%. This approach opens the door for clinical translation of NPs, expanding their therapeutic application to a wider range of chemical space of NPs and living organisms such as bacteria and fungi.