Quetiapine fumarate (QUE) is an antipsychotic agent with a chemical structure that is susceptible to degradation; therefore, it is important to study its stability using appropriate analytical tools. Knowledge of the stability profile of a drug is important because chemical degradation of its active component often results in a loss of potency, affecting its efficacy and safety. This current work reports degradation studies of QUE as drug substance, under different stress conditions such as oxidation, hydrolysis, heat, humidity and photolysis, by a stability-indicating LC method. The chemical stability was evaluated using a simple HPLC/diode array detection method, with a core-shell C18 column under isocratic conditions, which allows the separation of all primary degradation products (DPs) in a short run time. QUE was mainly degraded under oxidative and hydrolytic conditions, with the formation of three and two DPs, respectively, which were identified by electrospray ionization-tandem mass spectrometry. The method was properly validated in terms of linearity, accuracy, precision, selectivity, robustness and quantitation limit. Commercial tablets containing 25 mg of QUE were quantified, with results obtained within the United States Pharmacopeia limits. The proposed method is suitable to assess the stability and perform routine analysis of QUE in pharmaceutical samples.