Abstract: Zanthoxylum bungeanum Maxim. is an essential spice and medicinal plant in China. Zanthoxylum bungeanum Maxim. has a distinct bitterness due to 7-methoxylcoumarin. The bitterness of Zanthoxylum bungeanum Maxim. restricted the development and utilization of its products. This study aimed to explore the masking effect and mechanism of whey protein isolate on the bitterness of Zanthoxylum bungeanum Maxim.. The masking mechanism of the bitterness of Zanthoxylum bungeanum Maxim. by whey protein isolate was investigated using the method of sensory evaluation, electronic tongue and molecular docking technique with Zanthoxylum bungeanum Maxim. oleoresin as the matrix. The results indicated that whey protein isolate could significantly mask the bitterness of Zanthoxylum bungeanum Maxim. oleoresin. Furthermore, there was a mass concentration-effect relationship between bitterness reduction values of Zanthoxylum bungeanum Maxim. oleoresin and the additive amount of whey protein isolate. When the dosage of whey protein isolate was 1.00% and the concentration of Zanthoxylum bungeanum oleoresin was 0.5%, the reduction value of ΔBI was 1.8, indicating that the bitterness masking effect was good. The molecular docking model showed that 7-methoxycoumarin and β-lactoglobulin had 20 docking conformations in cluster 2, and the lowest binding free energy was −5.90 kcal/mol. Hence, cluster 2 was the most likely binding region for their interaction. It could be concluded that whey protein isolate could mask the bitterness of Zanthoxylum bungeanum Maxim. oleoresin by binding to 7-methoxycoumarin and preventing it from binding to bitter receptors. The results may provide a reference for the taste correction of Zanthoxylum bungeanum Maxim. products.