The huge amount of citrus peel produced worldwide represents an economic burden for society. However, this agricultural by-product is a rich source of natural molecules, potentially endowed with interesting pharmacological activities. In this regard, we decided to investigate if the polymethoxyflavones contained in citrus peel waste could be exploited as novel vasorelaxant agents. A hydroalcoholic blond orange () peel extract, obtained by ultrasonication, was partitioned in dichloromethane. Column chromatography allowed for the isolation of four polymethoxyflavones, namely, scutellarein tetramethyl ether, nobiletin, tangeretin, and sinensetin, identified by nuclear magnetic resonance (NMR) spectroscopy and UPLC-HRMS/MS and confirmed by multivariate curve resolution of NMR fractional spectra. The four molecules showed interesting in vitro vasorelaxant activity, at least, in part, due to the blockade of smooth muscle Ca1.2 channels. Molecular modeling and docking analysis elucidated the binding mode of the polymethoxyflavones at the homology model of the rat Ca1.2c subunit and provided the structural basis to rationalise the highest activity of scutellarein tetramethyl ether in the set and the dramatic effect of the additional methoxy group occurring in nobiletin and sinensetin. In conclusion, citrus peel can be considered a freely available, valuable source of vasoactive compounds worthy of pharmaceutical and/or nutraceutical exploitation.