The present study reports the degradation behavior of roflumilast (RFL), a new drug developed for the treatment of chronic obstructive pulmonary disease. The degradation of RFL was tested under various stress conditions as per the guidelines of the International Conference on Harmonization. The degradation products (DPs) of RFL were identified, characterized and in silico predictions were made of their pharmacokinetic properties, absorption, distribution, metabolism, excretion and toxicity (ADMET). RFL was subjected to various stress conditions including photodegradation, alkaline and acidic hydrolysis, oxidative and metallic degradation. After analysis by HPLC-DAD, the DPs were isolated by preparative TLC and characterized by high resolution mass spectrometry (HRMS), 1H NMR, 13C NMR and infrared (IR) spectroscopy. RFL tablets were prepared by the addition of solid stressing substances such as excipients and storage in an accelerated stability chamber (40 °C; 75% r.h.) for sixteen months. Resulting DPs from the tablets were analyzed by UFLC-QTOF. The most drastic degradation conditions for RFL were 5 M NaOH(aq), 6 M HCl(aq), 7.5% v/v peracetic acid, which resulted in the isolation of four DPs. However, milder degradation conditions (1 M NaOH(aq) and photolysis) generated six DPs (DP-1, 2, 3, 5, 7 and 8), and are more similar to the actual conditions the drug will be exposed. For tablets containing RFL exposed to an alkaline reagent, two DPs were formed: DP-1 and DP-11. Whereas RFL-containing tablets exposed to acid and oxidizing agents, formed one product DP-11. Forced degradation of RFL led to the formation of eleven DPs, seven of which have never been previously reported. RFL is stable under metallic stress and it is relatively stable during photodegradation testing. The UFLC-QTOF methodology detected a greater number of DPs that formed during the stress conditions tested when compared to the HPLC-DAD methodology. In silico prediction of the ADMET properties of the RFL degradation products and metabolites produced in this study are potentially hepatotoxic.