Drug release from four different poly(lactic-co-glycolic) acid (PLGA) microsphere formulations was evaluated under “real-time” (37 °C) and accelerated release testing conditions of elevated temperature (45, 53, 60 and 70 °C) and increase in flow rate (4–35 ml/min) using United States Pharmacopeia (USP) apparatus 4. Formulation 5 K (composed of low Mw PLGA) exhibited diffusion-controlled kinetics in “real-time”. Whereas, formulations 25 K, 28 K and 70 K (composed of medium and high Mw PLGA) followed erosion-controlled kinetics at 37 °C. Temperature-induced degradation of the microspheres was studied by monitoring drug release rates, change in molecular weight and morphological changes. Drug release rates at elevated temperature were used to predict “real-time” release applying the Arrhenius equation. The energy of activation for dexamethasone release from PLGA microspheres was calculated as 19.14 kcal/mol. Molecular weight change measured by gel permeation chromatography followed first order kinetics for both “real-time” and accelerated release. All four formulations exhibited morphological changes (such as surface pore closing and geometry change) at elevated temperature with consequent reduction in burst release.