Platelet-rich fibrin (PRF) is an autologous-derived bioactive material used in bone regeneration, consisting of a fibrin scaffold and its internal loading of growth factors, platelets, and leukocytes. PRF promotes vascular regeneration, enhances the proliferation and migration of osteoblast-related cells, and has immunomodulatory and antibacterial effects. It has excellent osteogenic potential and is widely used in bone tissue engineering and dentistry. However, PRF has limitations, and improving its biological properties is crucial. PRF is often combined with bone tissue engineering scaffolds to enhance its mechanical properties and delay degradation. This review systematically discusses the development of platelet-rich derivatives, the structure and biological properties of PRF, osteogenic mechanisms, applications, and optimization to broaden its clinical applications and guide its clinical translation. PRF is a solid 3D fibrin membrane containing a dense fibrin matrix abundant in platelets and growth factors, made mainly from whole blood without anticoagulants. PRF has a unique structure with three layers after centrifugation: superficial platelet-poor plasma (PPP), intermediate platelet-rich fibrin (PRF), and basal red blood cells (RBCs). PRF contains bioactive molecules, fibrin matrix, and cells, including PDGF, VEGF, TGF-β, BMP-1, and IGF. Cells include lymphocytes, macrophages, and platelets. PRF promotes angiogenesis and bone regeneration by releasing growth factors and cytokines over time. The release rate and duration of growth factors in PRF play a crucial role in bone regeneration. PRF has been shown to promote the expression of VEGF, PDGF, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) in endothelial cells and primary osteoblasts, promoting angiogenesis. PRF also enhances the proliferation and migration of human umbilical vein endothelial cells (HUVEC) and promotes tube formation through the EGFR signaling pathway. PRF promotes osteogenesis by activating various signaling pathways, including BMP/SMAD, TGF-β, ERK/MAPK, JNK/MAPK, Wnt, and Notch. PRF activates BMP receptors, triggers intracellular SMAD1/5/8 phosphorylation, induces Runx2 gene expression, and promotes osteogenic differentiation of BMSCs through the BMP-2/SMAD signaling pathway. PRF also enhances the proliferation, migration, and osteogenic differentiation of human bone marrow MSCs by activating the ERK/MAPK pathway. PRF has immunomodulatory effects by decreasing the activity of M1-type macrophages and promoting the activation of M2-type macrophages. PRF significantly inhibits the expression of M1-type macrophage markers, TNF-α, and IL-6, and inhibits the phosphorylation of p6Platelet-rich fibrin (PRF) is an autologous-derived bioactive material used in bone regeneration, consisting of a fibrin scaffold and its internal loading of growth factors, platelets, and leukocytes. PRF promotes vascular regeneration, enhances the proliferation and migration of osteoblast-related cells, and has immunomodulatory and antibacterial effects. It has excellent osteogenic potential and is widely used in bone tissue engineering and dentistry. However, PRF has limitations, and improving its biological properties is crucial. PRF is often combined with bone tissue engineering scaffolds to enhance its mechanical properties and delay degradation. This review systematically discusses the development of platelet-rich derivatives, the structure and biological properties of PRF, osteogenic mechanisms, applications, and optimization to broaden its clinical applications and guide its clinical translation. PRF is a solid 3D fibrin membrane containing a dense fibrin matrix abundant in platelets and growth factors, made mainly from whole blood without anticoagulants. PRF has a unique structure with three layers after centrifugation: superficial platelet-poor plasma (PPP), intermediate platelet-rich fibrin (PRF), and basal red blood cells (RBCs). PRF contains bioactive molecules, fibrin matrix, and cells, including PDGF, VEGF, TGF-β, BMP-1, and IGF. Cells include lymphocytes, macrophages, and platelets. PRF promotes angiogenesis and bone regeneration by releasing growth factors and cytokines over time. The release rate and duration of growth factors in PRF play a crucial role in bone regeneration. PRF has been shown to promote the expression of VEGF, PDGF, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) in endothelial cells and primary osteoblasts, promoting angiogenesis. PRF also enhances the proliferation and migration of human umbilical vein endothelial cells (HUVEC) and promotes tube formation through the EGFR signaling pathway. PRF promotes osteogenesis by activating various signaling pathways, including BMP/SMAD, TGF-β, ERK/MAPK, JNK/MAPK, Wnt, and Notch. PRF activates BMP receptors, triggers intracellular SMAD1/5/8 phosphorylation, induces Runx2 gene expression, and promotes osteogenic differentiation of BMSCs through the BMP-2/SMAD signaling pathway. PRF also enhances the proliferation, migration, and osteogenic differentiation of human bone marrow MSCs by activating the ERK/MAPK pathway. PRF has immunomodulatory effects by decreasing the activity of M1-type macrophages and promoting the activation of M2-type macrophages. PRF significantly inhibits the expression of M1-type macrophage markers, TNF-α, and IL-6, and inhibits the phosphorylation of p6