Traumatic heterotopic ossification (THO) is a pathological condition characterized by abnormal bone formation in non-skeletal tissues, commonly occurring after surgery or trauma. Current treatments, including non-steroidal anti-inflammatory drugs and surgery, are often hindered by adverse effects and high recurrence rates. In this study, we explore the potential of indomethacin-loaded PLGA microspheres (INDO-PLGA MPs) as a targeted therapeutic strategy for THO prevention. Through emulsifying solvent volatilization, sustained release of INDO was effectively achieved, with the 30% drug loading exhibiting optimal encapsulation efficiency and an ideal release profile. Cellular and animal experiments further confirm the excellent biocompatibility of INDO-PLGA MPs. In vitro and in vivo analyses revealed that these microspheres effectively inhibited osteogenic and chondrogenic differentiation, which are critical pathways driving the progression of THO. Notably, the 30% INDO-PLGA MPs exhibited optimal efficacy in reducing ectopic bone volume and delaying THO onset in a tenotomy and burn rat model. Collectively, our findings highlight the promising potential of PLGA microspheres in enhancing the localized and sustained delivery of INDO, providing effective prevention of THO and offering a transformative approach to its management.