As nanotechnology advances, metal oxide nanoparticles (MeONPs) increasingly come into contact with humans. The inhaled MeONPs cannot be effectively cleared by cilia or lung mucus. In the last decade, potential immune toxicity arising from exposure to MeONPs has been extensively debated, as lung macrophage is the main pathway for cleaning inhaled exogenous particles. However, their toxicity on lung macrophages has rarely been quantitatively predicted in silico due to the complexity of responses in macrophages and the intricate properties of MeONPs. Here, machine learning (ML) methods were used to establish models for quantitatively predicting the toxicity of MeONPs in macrophages. A multidimensional dataset including 240 data points covering the lethality, biochemical behaviors, and physicochemical properties of 30 MeONPs was obtained. ML models based on different algorithms with high prediction accuracy were constructed by addressing the issue of class imbalance during the training process. The models were verified by 10-fold cross-validation and external validation. The best-performed model has an R of 0.85 and 0.90 in the 10-fold cross-validation and external test set, respectively; and Q of 0.88 and 0.90 in the 10-fold cross-validation and test set, respectively. Five parameters that impact toxicity were identified and the toxicity mechanisms were elucidated by ML analysis. The prediction results can be used to fill the data gap in the risk assessment of nanomaterials. The framework offers valuable insights for designing and utilizing safe nanoparticles, as well as aiding in decision-making processes aimed at protecting the environment and public health.