This work was aimed to optimize the composition of microspheres of olanzapine to design long acting depot injection for the treatment of psychosis. Solvent evaporation method was used for the fabrication of microspheres. Different formulation variables for the solvent evaporation method, viz., effect of theoretical drug loading, type of surfactant and its concentration, temperature, volume of external phase and presence of salt in external aqueous phase, conditions and time of solvent evaporation and drying methodology were optimized. The microspheres were characterized for encapsulation efficiency, particle size, surface morphology, residual solvent content, drug release profile and drug release kinetics. The optimized formulation showed consistent drug release for upto 14 days time period.