Heterotopic ossification (HO) is a pathological condition characterized by the development of ectopic bone in soft tissues within the skeletal system. The nuclear transcription factor kappa B (NF-κB) signaling pathway plays a crucial role in HO, particularly in the initial inflammatory stage and chondrogenesis. NF-κB signaling interacts with the NLRP3 inflammasome, Sirtuin 1 (SIRT1), and AMP-activated protein kinase (AMPK) to drive inflammation. In the chondrogenesis stage, NF-κB signaling promotes chondrogenesis through interactions with mTOR, phosphatidylinositol-3-kinase (PI3K)/AKT, and other molecules, including R-spondin 2 (Rspo2) and SRY-box 9 (Sox9). In fibrodysplasia ossificans progressiva (FOP), a genetic form of HO, mutated ACVR1-induced NF-κB signaling exacerbates inflammation in macrophages and promotes chondrogenesis and osteogenesis in mesenchymal stem cells (MSCs) through interactions with smad signaling and mTOR signaling. The review highlights the molecular mechanisms of NF-κB signaling in HO and discusses potential therapeutic strategies. Key findings include the involvement of SIRT1, AMPK, and the NLRP3 inflammasome in the inflammatory response, and the role of mTORC1, BMP signaling, and integrin-mediated signaling in chondrogenesis and osteogenesis. The study also explores the complex interactions between these signaling pathways and their potential therapeutic targets. Overall, the review provides insights into the molecular mechanisms of NF-κB signaling in HO and suggests potential therapeutic approaches to treat this condition.Heterotopic ossification (HO) is a pathological condition characterized by the development of ectopic bone in soft tissues within the skeletal system. The nuclear transcription factor kappa B (NF-κB) signaling pathway plays a crucial role in HO, particularly in the initial inflammatory stage and chondrogenesis. NF-κB signaling interacts with the NLRP3 inflammasome, Sirtuin 1 (SIRT1), and AMP-activated protein kinase (AMPK) to drive inflammation. In the chondrogenesis stage, NF-κB signaling promotes chondrogenesis through interactions with mTOR, phosphatidylinositol-3-kinase (PI3K)/AKT, and other molecules, including R-spondin 2 (Rspo2) and SRY-box 9 (Sox9). In fibrodysplasia ossificans progressiva (FOP), a genetic form of HO, mutated ACVR1-induced NF-κB signaling exacerbates inflammation in macrophages and promotes chondrogenesis and osteogenesis in mesenchymal stem cells (MSCs) through interactions with smad signaling and mTOR signaling. The review highlights the molecular mechanisms of NF-κB signaling in HO and discusses potential therapeutic strategies. Key findings include the involvement of SIRT1, AMPK, and the NLRP3 inflammasome in the inflammatory response, and the role of mTORC1, BMP signaling, and integrin-mediated signaling in chondrogenesis and osteogenesis. The study also explores the complex interactions between these signaling pathways and their potential therapeutic targets. Overall, the review provides insights into the molecular mechanisms of NF-κB signaling in HO and suggests potential therapeutic approaches to treat this condition.