Long-acting injectable (LAI) suspensions are controlled drug delivery systems that provide sustained drug release over durations ranging from one to six months. Although it is recognized that the particle agglomeration behavior could play a critical role on product clinical performance, factors that can affect this behavior have not yet been fully understood. This study explores the impact of particle size modification techniques, shear force, and agglomeration state on the in vitro drug release of LAI suspensions. Depo-Provera 150® [medroxyprogesterone acetate (MPA)] was used as the model drug product. Five qualitative (Q1) and quantitative (Q2) equivalent MPA suspensions (FA, FB, FC, FD, FE) were prepared with formulation and processing differences. Physicochemical characterization, including particle size, morphology, sedimentation value, and viscosity, was conducted. The effects of shear force, induced by shaking, syringe usage, ultrasonication, and stirring, on the agglomeration behavior of the MPA suspensions were also investigated. In vitro dissolution studies were performed using a novel in-house adapter. Characterization revealed that particles in MPA suspensions exist as weak agglomerates, strong agglomerates, or primary particles. Formulations FA and FC, containing weak agglomerates, were sensitive to shear and showed slight variations in drug release rates. Formulation FB, containing strong agglomerates, resisted low to medium shear and exhibited faster-than-expected drug release due to de-agglomeration in surfactant-containing media. Formulations FD and FE, composed of primary particles, tended to agglomerate during dissolution, resulting in slower release rates. This research highlights the critical role of particle agglomeration and agglomeration behavior in understanding drug release from MPA suspension and other similar LAI suspensions. The findings emphasize the need for thorough characterization of particle states and their response to shear force to optimize LAI formulations for consistent and predictable in vitro drug release.