This research focuses on the proteolytic capacity of Spirulina platensis and their hypocholesterolemic activity via the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR) inhibitory activity. To select suitable proteases for releasing peptides with high HMGR-inhibiting activity from S. platensis, eight commonly used commercial proteases were used in protease hydrolysis under high hydrostatic pressure (HHP, 100 MPa or 0.1 MPa) at 50 °C for 24 h. The Peptidase R group had the highest inhibitory capacity (67%). First, S. platensis was fermented with seven mixed lactic acid bacteria for 5 h at 42 °C. This was followed by the addition of Peptidase R under high hydrostatic pressure (100 MPa at 50 °C) for 0–6 h of enzymatic hydrolysis (HHP-FH-PR6) to determine the hydrolytic capacity of S. platensis protein. As the hydrolysis time extended to 6 h, the peptide content increased from 96.8 mg/mL to 339.8 mg/mL, and the free amino acid content increased from 24 mg/mL to 115.2 mg/mL, while inhibition of HMGR increased from 67.0% to 78.4%. In an experimental simulation of in vitro gastrointestinal digestion, the IC50 of HHP-FH-PR6G on HMGR was 3.5 μg peptide/mL. Peptides with inhibitory activity on HMGR were purified, and their sequences were identified as Arg-Cys-Asp and Ser-Asn-Val (IC50: 6.9 and 20.1 μM, respectively).