Microspheres have gained much attention from pharmaceutical and medical industry due to the excellent biodegradable and long controlled-release characteristics. However, the drug release behavior of microspheres is influenced by complicated formulation and manufacturing factors. The traditional formulation development of microspheres is intractable and inefficient by the experimentally trial-and-error methods. This research aims to build a prediction model to accelerate microspheres product development for small-molecule drugs by machine learning (ML) techniques. Two hundred eighty-six microsphere formulations with small-molecule drugs were collected from the publications and pharmaceutical company, including the dissolution temperature at both 37 ℃ and 45 ℃. After the comparison of fourteen ML approaches, the consensus model achieved accurate predictions for the validation set at 37 ℃ and 45 ℃ (R² = 0.880 vs. R² = 0.958), indicating the good performance to predict the in vitro drug release profiles at both 37 ℃ and 45 ℃. Meanwhile, the models revealed the feature importance of formulations, which offered meaningful insights to the microspheres development. Experiments of microsphere formulations further validated the accuracy of the consensus model. Furthermore, molecular dynamics (MD) simulation provided a microscopic view of the preparation process of microspheres. In conclusion, the prediction model of microsphere formulations for small-molecule drugs was successfully built with high accuracy, which is able to accelerate microspheres product development and promote the quality control of microspheres for the pharmaceutical industry.