Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising target for the treatment of hypercholesterolemia. In fact, the main role of PCSK9 is the degradation of low-density lipoprotein receptor (LDLR) protein with an increase of the LDL cholesterol levels. Some natural mutations in PCSK9 affect its affinity for the LDLR. In particular, the gain of function (GOF) mutant D374Y binds more avidly to the LDLR than the wild-type (WT) PCSK9 with an approximately tenfold increased capacity of reducing the LDLR protein level. In this panorama, lupin protein hydrolysates, obtained by the hydrolysis with pepsin and trypsin, show complementary hypocholesterolemic effects through the modulation of both 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) and PCSK9 targets. With the aim of identifying lupin peptides able to impair the binding of PCSK9WT and/or PCSK9D374Y to the LDLR, biochemical and cellular experiments were assessed. Results suggest that both P5 (LILPHKSDAD) and T9 (GQEQSHQDEGVIVR) show an in vitro hypocholesterolemic effect through the modulation of both HMGCoAR and PCSK9WT activities, whereas only T9 is active also against the PCSK9D374Y. Both P5 and T9 display a dual-inhibitory cholesterol-lowering behavior. This unique feature frames them in the context of multifunctional peptides with potential application for the prevention of cardiovascular disease.