During this phytochemical study, 13 compounds from the bark of Salix cinerea L. were isolated and their structures elucidated. These included two salicylic alcohol derivatives, one flavonol, two phenylpropanoids, two flavan-3-ols, two dimeric procyanidins, two dimeric prodelphinidins, and a unique ester of catechin (3-O-(1-hydroxy-6-oxo-2-cyclohexen-1-carboxylic acid), HCH-catechin). Furthermore, seasonal variations in the composition of Salix cortex regarding proanthocyanidins (PA) and the degree of polymerization were examined using NMR spectroscopy, revealing an increase in polymerization throughout the growing season 2020 associated with a consistent hydroxylation pattern in the B-ring. The isolated HCH-catechin was tested in vitro for its inhibitory effect on TNF-α-induced ICAM-1 expression in human microvascular endothelial cells (HMEC-1). A 24 h treatment with a 25 µM solution of HCH-catechin significantly reduced ICAM-1 expression (83.7 ± 3.2%) compared to unsubstituted catechin (97.9 ± 4.4%). Additionally, during a mass-spectrometric screening, numerous HCH adducts within the PA fraction could be identified, allowing for the proposition of a characteristic fragmentation pattern. This study establishes a foundation for a comprehensive assessment of the phenolic, PA-rich fraction in willow bark, particularly the occurrence of HCH adducts, which may contribute to the medicinal properties of Salicis cortex. Findings on seasonal variations and mass spectrometric profiling offer new insights into the quality standards for Salicis cortex as a medicinal remedy.