Ibuprofen is a widely utilised analgesic anti-inflammatory drug. It is sensitive to oxidation and photodegradation. In this work, the oxidative and thermal degradations were investigated. The treatments adopted allowed the detection of 13 degradation products, seven of which have never been reported: hydratropic acid, 4-ethylbenzaldehyde, 4-(1-carboxyethyl)benzoic acid, 1-(4-isobutylphenyl)-1-ethanol, 2-[4-(1-hydroxy-2-methylpropyl)phenyl]propanoic acid, 1-isobutyl-4-vinylbenzene, 4-isobutylphenol. For 1-(4-isobutylphenyl)-1-ethanol, the in vitro toxic effects have already been described in the literature. To detect all degradation products, two RP-HPLC methods and a GC-MS procedure were developed or modified from the official monographs. The identification was conducted by evaluating chromatographic and spectral data and the structural attributions were confirmed by simple and univocal synthesis. Moreover, the actual presence of these molecules in marketed medicinal products was investigated.