The aim of the present study was to formulate and evaluate sustained-release microspheres of Desvenlafaxine for the management and treatment of depression. Sustained release microspheres of Desvenlafaxine were prepared by solvent evaporation technique by using natural polymers such as chitosan and sodium alginates. Further, the sustained-release microspheres were evaluated for flow characteristics, entrapment efficiency,percentage yield, particle size analysis, zeta potential analysis, scanning electron microscopy, in-vitro drug release, and kinetics of drug release.In-vitro, drug release studies were carried out in a phosphate buffer solution (pH7.4).Theprepared microspheres show good encapsulation efficiency and the particle size of the microspheres ranges from 34.6μm to 60.6 μm. The IR spectrum revealed that there was no interaction between the drug and the polymer.Micromeritics studies showed good flow properties and maximum entrapment efficiency was found to be 82.87% from the chitosan F4 DSV microsphere. Among the microsphere batches, F4 of chitosan was observed as an optimized batch.The in-vitro drug release of the F4 formulation prepared by using chitosan was found to be 94.60%, which sustained the action of the drug for 24 hours and its stability study indicates that these microspheres were stable at selected temperature and humidity while storage for 60 days without any significant changes in drug release characteristics. The sustained-release microspheres were formulated successfully and results clearly stated that Desvenlafaxine microspheres were safe and effective drug delivery over an extended period, which can increase bioavailability,patient compliance, and decrease dosing frequency.