TLC combined with densitometry was used, and chromatographic conditions were developed to determination both fluoxetine and sertraline in pharmaceuticals. The mobile phase with the composition of acetone, chloroform, and ammonia (10:5:1, v/v) allowed separation of the most degradation products of sertraline and fluoxetine from all nineteen used in the study of mobile phases. Therefore, this mobile phase was selected as optimal for the analysis of sertraline and fluoxetine in pharmaceutical formulations. The RF values of sertraline and fluoxetine differ from the degradation products of fluoxetine and sertraline. Therefore, the developed chromatographic conditions can be used for the simultaneous determination of fluoxetine and sertraline. Confirmation of the identity of the active substance can be made on the basis of the compliance of the RF values and the spectrodensitograms of the substance from the pharmaceutical preparation and the standard of fluoxetine or sertraline, respectively. The developed method was simple, economical, specific, precise, accurate, sensitive, and robust, with a good range of linearity for the quantification of fluoxetine and sertraline in pharmaceutical preparations. TLC in combination with densitometry can be recommended for the analysis of fluoxetine and sertraline in the absence of HPLC in the laboratory or to confirm results obtained with other analytical techniques.