Seafood consumption has a great demand in the world due to its array of health benefits. Marine-derived bioactive peptides and hydrolysates have been found to have multifunctional health benefits. In this study, inhibitory effects of blue mussel hydrolysates, including blue mussel Alcalase® hydrolysate (BMAH) and blue mussel-pepsin hydrolysate (BMPH), on foam cell formation in ox-LDL-induced RAW264.7 macrophages were investigated. BMAH inhibited lipid accumulation evidenced by Oil Red O staining. Its inhibitory effect was higher than that of BMPH. BMAH positively modulated levels of total cholesterol, free cholesterol, and cholesterol ester in model cells. It suppressed cholesterol influx by downregulating SR-A1 and CD36 expression, but increased cholesterol efflux by upregulating ABCA-1 and ABCG-1 expression. In addition, ox-LDL treated RAW264.7 macrophages produced inflammatory responses and oxidative stress during foam cell formation. However, BMAH treatment significantly ameliorated proinflammatory cytokines production (TNF-α, IL-6, and IL-1β) by inhibiting NF-κB nuclear translocation. Moreover, BMAH inhibited intracellular reactive oxygen species (ROS) generation by activating HO-1/Nrf2 signaling pathway in ox-LDL-treated RAW264.7 macrophages. Taken together, these results suggest that BMAH might be useful as an ingredient of functional foods to ameliorate the development of atherosclerosis.