The NF-κB pathway consists of two main pathways: the canonical and non-canonical. The canonical pathway is activated by various stimuli, leading to the rapid but transient activation of proinflammatory genes and serving as a critical mediator of inflammatory responses. The non-canonical pathway is activated through a few TNF receptor superfamily members and involves protein synthesis, resulting in a slow but persistent activation, which is essential for immune cell development and homeostasis. Both pathways are tightly regulated, with ubiquitination playing a vital role. Dysregulated NF-κB activity is linked to inflammation-related diseases and cancers, making it a potential therapeutic target. This review summarizes the mechanisms of NF-κB pathway regulation and the potential therapeutic applications of inhibiting NF-κB signaling in cancer and inflammatory diseases. The canonical NF-κB pathway is activated by various stimuli, including TLRs, IL-1R, and TNF receptors. Activation involves the phosphorylation and degradation of IκB proteins, releasing NF-κB dimers to translocate to the nucleus and activate target genes. The non-canonical pathway is activated through a few TNF receptor superfamily members, with NIK playing a key role. Activation of the non-canonical pathway involves the processing of p100 into p52, which forms a dimer with RelB to translocate to the nucleus. The canonical NF-κB pathway is involved in immune responses and is a potential target for the treatment of inflammation-related diseases and cancers. Inflammation and cancer are closely linked, with chronic inflammation contributing to cancer development. The tumor-promoting effects of canonical NF-κB include promoting tumor growth, survival, and angiogenesis. Targeting NF-κB in cancer therapy has shown promise, with anti-inflammatory drugs and antibodies against TNF-α being used in clinical trials. However, long-term use of NF-κB inhibitors may lead to immunodeficiency, so they should be used in short periods. The non-canonical NF-κB pathway is also involved in immune cell development and is regulated by NIK and the NIK-IKKα axis. The processing of p100 is a central event in the non-canonical pathway, involving phosphorylation and ubiquitination. The non-canonical pathway is negatively regulated through deubiquitination and degradation of NIK. Overall, both canonical and non-canonical NF-κB pathways are essential for immune responses and are potential targets for the treatment of diseases.The NF-κB pathway consists of two main pathways: the canonical and non-canonical. The canonical pathway is activated by various stimuli, leading to the rapid but transient activation of proinflammatory genes and serving as a critical mediator of inflammatory responses. The non-canonical pathway is activated through a few TNF receptor superfamily members and involves protein synthesis, resulting in a slow but persistent activation, which is essential for immune cell development and homeostasis. Both pathways are tightly regulated, with ubiquitination playing a vital role. Dysregulated NF-κB activity is linked to inflammation-related diseases and cancers, making it a potential therapeutic target. This review summarizes the mechanisms of NF-κB pathway regulation and the potential therapeutic applications of inhibiting NF-κB signaling in cancer and inflammatory diseases. The canonical NF-κB pathway is activated by various stimuli, including TLRs, IL-1R, and TNF receptors. Activation involves the phosphorylation and degradation of IκB proteins, releasing NF-κB dimers to translocate to the nucleus and activate target genes. The non-canonical pathway is activated through a few TNF receptor superfamily members, with NIK playing a key role. Activation of the non-canonical pathway involves the processing of p100 into p52, which forms a dimer with RelB to translocate to the nucleus. The canonical NF-κB pathway is involved in immune responses and is a potential target for the treatment of inflammation-related diseases and cancers. Inflammation and cancer are closely linked, with chronic inflammation contributing to cancer development. The tumor-promoting effects of canonical NF-κB include promoting tumor growth, survival, and angiogenesis. Targeting NF-κB in cancer therapy has shown promise, with anti-inflammatory drugs and antibodies against TNF-α being used in clinical trials. However, long-term use of NF-κB inhibitors may lead to immunodeficiency, so they should be used in short periods. The non-canonical NF-κB pathway is also involved in immune cell development and is regulated by NIK and the NIK-IKKα axis. The processing of p100 is a central event in the non-canonical pathway, involving phosphorylation and ubiquitination. The non-canonical pathway is negatively regulated through deubiquitination and degradation of NIK. Overall, both canonical and non-canonical NF-κB pathways are essential for immune responses and are potential targets for the treatment of diseases.