Background/Objectives: Poly(lactic-co-glycolic acid) (PLGA) microspheres are widely used in long-acting injectable (LAI) formulations because PLGA exhibits well-established biocompatibility and undergoes controlled hydrolytic degradation into metabolizable byproducts. However, optimization of microspheres typically requires time-consuming in vitro testing. Therefore, we developed a predictive machine learning model for early-stage and full time-dependent release profiles of drug-loaded PLGA microspheres. Methods: Using a published dataset comprising 321 release profiles from 89 drugs, we first developed a classification model to identify slow-release behavior (≤20% release within 3 days) and subsequently integrated the predicted early-release probability into a regression model to estimate cumulative release over time. Results: Among tree-based ensemble models, XGBoost achieved the lowest mean absolute error (MAE = 0.126) and highest Pearson correlation coefficient (r = 0.831). SHapley Additive exPlanations (SHAP) analysis revealed that drug and polymer molecular weight, predictive slow-release probability, and polymer concentration substantially influence release behavior. We also assessed this framework with external datasets. Drug release data for olaparib-loaded PLGA microspheres were obtained in-house, whereas those for semaglutide-based microspheres were obtained from the published literature. In both datasets, this framework demonstrated low MAE values (0.096 and 0.068, respectively). Conclusions: This suggests that the proposed framework can predict in vitro drug release and support efficient optimization of PLGA-based LAI formulations.