In an effort to develop potent anti-inflammatory agents, a series of novel chroman derivatives including acyclic amidochromans, chromanyl esters and chromanyl acrylates have been designed, synthesized and fully characterized. These chroman analogues were screened for their anti-inflammatory activities through inhibition of the TNF-α-induced ICAM-1 expression on human endothelial cells. A structure–activity relationship was also established and it has been found that in the case of carboxy chromans and amidochromans, the chain length of the amide moiety, branching of the side chain and the presence of the substituents on the phenyl ring have significant effects on their inhibitory activities, while in chromanyl acrylates, the number of methoxy groups, their relative positions on the phenyl ring, and presence of functional groups in the α,β-unsaturated ester moiety played a critical role on their activities. Compound 14 (N-hexyl-7-hydroxy-2,2-dimethylchromane-6-carboxamide) was found to be the most potent compound in inhibiting the TNF-α-induced expression of ICAM-1 on endothelial cells.