Hypercholesterolemia is a major risk for the development of cardiovascular diseases (CVDs), the main cause of mortality worldwide, and it is characterized by high levels of circulating cholesterol. The drugs currently available for hypercholesterolemia control have several side effects, so it is necessary to develop new effective and safer therapies. Seaweeds serve as sources of several bioactive compounds with claimed beneficial effects.Eisenia bicyclis(Aramé) andPorphyra tenera(Nori) are edible seaweeds that were previously recognized as rich in bioactive compounds. In the present study, we aim to evaluate the anti-hypercholesterolemia effect of these two seaweed extracts and their health potential. Both extracts, but more efficiently Aramé extract, have liver 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitory activity as well as the capability to reduce approximately 30% of cholesterol permeation through human Caco-2 cells by simulating the intestinal lining, which is a target for hypercholesterolemia treatments. An untargeted metabolomic assay on human intestinal Caco-2 and liver Hep-G2 cell lines exposed to Aramé and Nori extracts revealed changes in the cells’ metabolism, indicating the extracts’ health beneficial effects. The metabolic pathways affected by exposure to both extracts were associated with lipid metabolism, such as phospholipids, and fatty acid metabolism, amino acid pathways, cofactors, vitamins, and cellular respiration metabolism. The effects were more profound in Aramé-treated cells, but they were also observed in Nori-exposed cells. The metabolite modifications were associated with the protection against CVDs and other diseases and to the improvement of the cells’ oxidative stress tolerance. The results obtained for the anti-hypercholesterolemia properties, in addition to the revelation of the positive impact on cell metabolism, offer an important contribution for further evaluation of these seaweed extracts as functional foods or for CVD prevention.