Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a central regulator of cholesterol homeostasis, yet the shallow PCSK9–LDLR interface has hindered small-molecule inhibitor development. Using mixed-solvent molecular dynamics (MSMD) simulations with six diverse probes, we identified a novel cryptic allosteric pocket within the C-terminal domain (CTD), ∼60 Å from the LDLR-binding site. Pocket opening was facilitated by the disruption of key salt bridges, notably R580–E612, and observed across all probe conditions. Network-based correlation analyses revealed communication pathways linking this CTD pocket to the LDLR-binding interface with functionally important residues such as H574 and V610 involved. These results uncover a previously uncharacterized druggable allosteric site in PCSK9 and provide mechanistic insight into long-range allosteric modulation. The findings lay a foundation for the rational design of next-generation PCSK9 inhibitors, offering new opportunities for hypercholesterolemia therapy.