The proto-oncogene serine/threonine kinase PIM2 is a critical regulator of cell proliferation, survival, and tumor progression and represents an attractive therapeutic target for several cancers. In this study, an integrated machine learning–guided computational pipeline was developed to identify potential PIM2 inhibitors by combining quantitative structure–activity relationship (QSAR) modeling, virtual screening, molecular docking, molecular dynamics (MD) simulations, and pharmacokinetic prediction. Bioactivity data for PIM2 inhibitors were retrieved from the ChEMBL database, yielding 5953 compounds. After data cleaning, structural standardization, and removal of duplicates and invalid entries, a curated dataset of 1584 compounds was obtained for QSAR modeling. To address dataset imbalance, the Synthetic Minority Oversampling Technique (SMOTE) was applied before model development. Twelve molecular fingerprint descriptors were generated and used to construct 180 QSAR models using five machine learning algorithms, including Random Forest (RF), Extreme Gradient Boosting (XGBoost), Support Vector Regression (SVR), k-Nearest Neighbors (KNN), and Multilayer Perceptron (MLP). Among these models, the Random Forest–fingerprint model demonstrated the best predictive performance, achieving a mean R2 of 0.971 with low prediction errors (RMSE = 0.271; MAE = 0.125) across training, testing, and cross-validation datasets. The optimized model was subsequently applied to virtual screening of multiple chemical libraries, including FDA-approved drugs, natural product databases, and commercial compound collections. Several promising candidates were identified, including TCMBANKIN000009 (emetine), Amb28533044 (4,6′-Anhydrooxysporidinone), NPC170963 (Lysophosphatidylcholine (15:0)), NPC262768 (Endosulfan), and NPC469603 (8-hydroxyircinialactam A). Molecular docking showed that these compounds bind within the ATP-binding pocket of PIM2 kinase, forming interactions with key residues such as Lys62, Asp125, Asp128, and Glu168. Subsequent molecular dynamics simulations confirmed the stability of selected complexes, demonstrating reduced residue fluctuations, stable protein compactness, and persistent intermolecular interactions during the simulation. Furthermore, ADMET prediction suggested favorable pharmacokinetic and toxicity profiles for several compounds. Collectively, these findings highlight the potential of the identified molecules as promising PIM2 inhibitor candidates, providing valuable leads for future experimental validation and anticancer drug development.