This review discusses the roles of NF-κB and STAT3 in liver inflammation and cancer. NF-κB, a family of transcription factors, plays a crucial role in maintaining liver homeostasis by regulating cell survival, immunity, and inflammation. In hepatocytes, IKKβ-dependent NF-κB signaling promotes hepatocyte survival and inhibits tumor development. However, in other models, NF-κB can promote tumor development by maintaining an inflammatory microenvironment. STAT3, another transcription factor, is activated by various cytokines and growth factors, including IL-6, and is often constitutively activated in human HCC. STAT3 is essential for tumorigenesis in mouse models and is a promising therapeutic target. The review also highlights the crosstalk between NF-κB and STAT3, where NF-κB can prevent STAT3 activation by producing antioxidants, and STAT3 can contribute to NF-κB activation by acetylating RelA/p65. Overall, the activation of NF-κB and STAT3 pathways is critical for liver inflammation and cancer progression, making them potential therapeutic targets.This review discusses the roles of NF-κB and STAT3 in liver inflammation and cancer. NF-κB, a family of transcription factors, plays a crucial role in maintaining liver homeostasis by regulating cell survival, immunity, and inflammation. In hepatocytes, IKKβ-dependent NF-κB signaling promotes hepatocyte survival and inhibits tumor development. However, in other models, NF-κB can promote tumor development by maintaining an inflammatory microenvironment. STAT3, another transcription factor, is activated by various cytokines and growth factors, including IL-6, and is often constitutively activated in human HCC. STAT3 is essential for tumorigenesis in mouse models and is a promising therapeutic target. The review also highlights the crosstalk between NF-κB and STAT3, where NF-κB can prevent STAT3 activation by producing antioxidants, and STAT3 can contribute to NF-κB activation by acetylating RelA/p65. Overall, the activation of NF-κB and STAT3 pathways is critical for liver inflammation and cancer progression, making them potential therapeutic targets.