In this work, the design, synthesis, and structure-activity relationships of a novel array of geranyloxy and farnesyloxy 3-acetylcoumarins were reported as potent soybean 15-lipoxygenase inhibitors. Among the prepared coumarins, 7-farnesyloxy-3-acetylcoumarin (12b) was found to be the most potent inhibitor by IC 50 = 0.68 μM while O-geranyl substituents at positions 5 and 6 of 3-acetylcoumarin (10a and 11a)were not inhibitors. Using docking studies, the binding affinity and the preferred pose of synthetic compounds were considered. It was found that lipoxygenase inhibitory activity and prenyl length chain were directly related. The hydrophobic cavity of the enzyme was more effectively occupied by the farnesyl moiety of the potent inhibitor 12b rather than other derivatives. Also, with this pose of farnesyl chain in 7-farnesyloxy-3-acetylcoumarins, the acetyl group could be directed to the hydrophilic pocket in the active site.