Edaravone is an antioxidant drug used for the treatment of amyotrophic lateral sclerosis. Edaravone has been shown to react with aldehydes, such as 6-formylpterin. We investigated the reaction of edaravone with vanillin (used as a model aromatic aldehyde) to evidence the reaction products formed in an aqueous solution. Mono- and bis-adducts vanillin-(edaravone)1-2 were characterized by high-performance liquid chromatography coupled to high-resolution mass spectrometry. Kinetic analysis revealed that the bis-adduct vanillin-(edaravone)2 formed more intensely and more rapidly than the mono-adduct vanillin-(edaravone)1. Decay rates of 2.4 and 3.4 μM/min were calculated for vanillin and edaravone, respectively. The Michael addition of a second edaravone molecule onto the vanillin-(edaravone)1 hybrid corresponds to a facile reaction compared to the initial Knoevenagel-type condensation between edaravone and vanillin. However, the bis-adduct vanillin-(edaravone)2 can decompose in solution to provide the mono-adduct and regenerate small amounts of edaravone and vanillin. The regeneration of vanillin from vanillin-(edaravone)2 was kinetically characterized. We compared the condensation of edaravone with fifteen aromatic aldehydes, to show that only vanillin and 3-methoxy-benzaldehyde can react easily with edaravone, the other aromatic aldehydes being less or not reactive. The study opens perspectives to apprehend the reactivity of edaravone with biologically relevant aldehydes.