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Macroalgae polysaccharides are phytochemicals that are beneficial to human health. In this study, response surface methodology was applied to optimize the extraction procedure of <i>Pyropia yezoensis</i> porphyran (PYP). The optimum extraction parameters were: 100 °C (temperature), 120 min (time), and 29.32 mL/g (liquid–solid ratio), and the maximum yield of PYP was 22.15 ± 0.55%. The physicochemical characteristics of PPYP, purified from PYP, were analyzed, along with its lipid-lowering effect, using HepG2 cells and <i>Drosophila melanogaster</i> larvae. PPYP was a β-type sulfated hetero-rhamno-galactan-pyranose with a molecular weight of 151.6 kDa and a rhamnose-to-galactose molar ratio of 1:5.3. The results demonstrated that PPYP significantly reduced the triglyceride content in palmitic acid (PA)-induced HepG2 cells and high-sucrose-fed <i>D. melanogaster</i> larvae by regulating the expression of lipid metabolism-related genes, reducing lipogenesis and increasing fatty acid β-oxidation. To summarize, PPYP can lower lipid levels in HepG2 cells and larval fat body (the functional homolog tissue of the human liver), suggesting that PPYP may be administered as a potential marine lipid-lowering drug.