A sensitive, selective, precise and stability-indicating high-performance thin-layer chromatographic (HPTLC) method for analysis of sertraline hydrochloride in the bulk drug and in formulations has been established and validated. Aluminum foil HPTLC plates precoated with silica gel 60F254 as stationary phase were used with toluene-ethyl acetate-ethanol-ammonia 8:2:0.5:0.1 (ν/ν). A compact spot was obtained for sertraline hydrochloride (RF 0.33 ± 0.02). Densitometric analysis was performed in absorbance mode at 273 nm. Regression analysis of calibration data revealed a good linear relationship (r2 = 0.9996 ± 0.02) between response and concentration over the range 2000–12000 ng per band. The method was validated for accuracy, precision, linearity, limits of detection and quantification, and robustness. Sertraline hydrochloride was subjected to acidic and alkaline hydrolysis, oxidation, dry heat treatment, and photodegradation. Peaks of degradation products were well resolved from that of the pure drug and had significantly different RF values. Statistical analysis showed the method enabled repeatable and selective analysis of sertraline hydrochloride. The method can be used for routine quantitative analysis of sertraline hydrochloride in the bulk drug and in formulations.