The aim of this study was to prepare injectable depot formulations of Olanzapine using four poly(D,L-lactide-co-glycolide) (PLGA) polymers of varying molecular weight and copolymer composition, and evaluate in vivo performance in rats. In vivo release profiles from the formulations were governed chiefly by polymer molecular weight and to a lesser extent, copolymer composition. Formulations A and B, manufactured using low molecular weight PLGA and administered at 10 mg/kg dose, released drug within 15 days. Formulation C, prepared from intermediate molecular weight PLGA and administered at 20 mg/kg dose, released drug in 30 days, while Formulation D, manufactured using a high molecular weight polymer and administered at 20 mg/kg dose, released drug in 45 days. A simulation of multiple dosing at 7- and 10-day intervals for Formulations A and B revealed that steady state was achieved within 7-21 days and 10-30 days, respectively. Similarly, simulations at 15-day intervals for Formulations C and D indicated that steady state levels were reached during days 15-45. Overall, steady state levels for 7-, 10-, or 15-day dosing ranged between 45 and 65 ng/mL for all the formulations, implying that Olanzapine PLGA microspheres can be tailored to treat patients with varying clinical needs.