Antioxidant phytochemicals play a key role in oxidative stress control and in the prevention of related disorders, such as premature aging, degenerative diseases, diabetes, and cancer. The aim of this study was to investigate the potential antioxidant activity and the phytochemical profile of Senecio clivicolus Wedd., a perennial shrub, belonging to the Asteraceae family. Despite the wide interest of this family, this specie has not been investigated yet. S. clivicolus aerial parts were extracted with 96% ethanol. Then, the ethanol extract was fractionated by liquid/liquid extraction using an increasing solvents polarity. Total polyphenol and terpenoid contents were measured. Moreover, the antioxidant activity was evaluated by six different complementary in vitro assays. The Relative Antioxidant Capacity Index (RACI) was used to compare data obtained by different tests. The sample showing the highest RACI was subjected to characterization and quantitation of its phenolic composition using LC-MS/MS analysis. The ethyl acetate fraction, investigated by LC-MS/MS analysis, showed 30 compounds, most of them are chlorogenic acid and flavonoid derivatives. To the best of our knowledge, this is the first report about the evaluation of antioxidant activity and phytochemical profile of S. clivicolus, underlying the importance of this species as a source of health-promoting phytochemicals.