High-Density Lipoprotein (HDL) not only mediates reverse cholesterol transport in the periphery but also significantly influences Blood-Brain Barrier (BBB) function within the central nervous system by regulating lipid metabolism, inflammatory responses, oxidative stress, A beta trans-barrier clearance, and endothelial nitric oxide signaling. Variations in structural composition and biological properties between plasma HDL and brain-derived HDL-like particles enable them to perform both synergistic and distinct roles in maintaining cholesterol homeostasis, protecting tight junctions, regulating barrier permeability, facilitating A beta efflux, and stabilizing the neurovascular unit. Key components such as ApoA-I, the ApoM/Sphingosine-1-Phosphate (S1P) signaling axis, and ApoE preserve BBB integrity by enhancing endothelial and pericyte functions, stabilizing intercellular junctions, inhibiting matrix metalloproteinase activity, and reducing neuroinflammation. Additionally, HDL/HDL-like particles alleviate barrier stress by facilitating the clearance of metabolic waste through the glymphatic system. Existing research collectively suggests that HDL-like particles, as a multifaceted regulator of BBB homeostasis, play a crucial role in maintaining neurological health and influencing disease processes.