p38α is a mitogen-activated protein kinase (MAPK), and the signaling pathways involved are closely related to the inflammation, apoptosis and differentiation of cells, which also makes it an attractive target for drug discovery. With the high efficiency and low cost, virtual screening technology is becoming an indispensable part of drug development. In this study, a novel multi-stage virtual screening method based on machine learning, molecular docking and molecular dynamics simulation was developed to identify p38α MAPK inhibitors from natural products in ZINC database, which improves the prediction accuracy by considering and utilizing both ligand and receptor information compared to any individual approach. Ultimately, we screened out two candidate inhibitors with acceptable ADMET properties (ZINC4260400 and ZINC8300300). Among the generated machine learning models, Random Forest (RF) and Support Vector Machine (SVM) performed better, with the area under the receiver operating characteristic curve (AUC) values of 0.932 and 0.931 on the test set, as well as 0.834 and 0.850 on the external validation set. In addition, the results of molecular docking and ADMET prediction showed that two compounds with appropriate pharmacokinetic properties had binding free energies less than -8.0 kcal/mol for the target protein, and the results of molecular dynamics simulations further confirmed that they were stable during the process of inhibition.