For the first time the volatile fraction of coffee silverskin has been studied focusing on odor-active compounds detected by gas chromatography-olfactometry/flame ionization detector (GC-O/FID) system. Two approaches, namely headspace (HS) analysis by solid-phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS) and odor-active compounds analysis by gas chromatography-olfactometry/flame ionization detector (GC-O/FID), have been employed to fully characterize the aroma profile of this by-product. This work also provided an entire characterization of the bioactive compounds present in coffee silverskin, including alkaloids, chlorogenic acids, phenolic acids, flavonoids, and secoiridoids, by using different extraction procedures and high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) system. Coffee silverskin was shown to be a good source of caffeine and chlorogenic acids but also of phenolic acids and flavonoids. In addition, the fatty acid composition of the coffee silverskin was established by GC-FID system. The results from this research could contribute to the development of innovative applications and reuses of coffee silverskin, an interesting resource with a high potential to be tapped by the food and nutraceutical sector, and possibly also in the cosmetics and perfumery.