The purpose was to design and evaluate Fluoxetine orodispersible tablets (FLX ODTs) that characterized by, fast drug release with acceptable taste. FLX ODTs were prepared by direct compression after complexation of FLX with β-cyclodextrin (β-CD) for taste masking, using Crospovidone (CP), croscarmellose sodium (Ac-di-sol), sodium starch glycolate (SSG) and indion (as superdisintegrants). The powder blend was evaluated for pre-compression parameters. Also, the prepared tablets were evaluated for post-compression parameters. The selected tablet formulations based upon drug release at 40 sec and acceptable release pattern were investigated for accelerated stability testing and for comparative in vivo study with a marketed product. Results showed that all powder blends had good flow properties and all the prepared tablets complied with the pharmacopeial requirements for uniformity of content, weight, friability, and hardness. Also, all the tablets acquired acceptable taste after complexation. Order of release of the drug, regarding superdisintegrants used, was as in the following descending order: CP> Ac-di-sol> SSG> indion. Accelerated stability study of selected formulation F2 and F6 showed that; there was no considerable change in physical properties, drug content and percentage drug release, also the in vivo study proved the effectiveness of FLX ODTs as anti-depressant. The results obtained showed a promising potential of ODTs containing a specific ratio of superdisintegrants and prepared by complexation method for the effective treatment of depression.