Nuclear Factor-κappa B (NF-κB) is a family of critical transcription factors of the inflammatory pathway and plays an imperative role in the progression of various cancers such as breast, lung, liver, pancreatic, prostate and multiple types of lymphoma. NF- κB develops an inherent relationship between inflammation and cancer. It is a crucial factor that controls the ability of malignant and pre-neoplastic cells to prevent programmed cell death-based tumor-surveillance channels. Due to its high significance in the onset and progression of various cancers, it has become an excellent target for cancer therapy. The emerging targeted therapies provide a lot of hope, whereby a single protein or generally the target enzyme is completely blocked. Several natural compounds have shown anticancer and anti-inflammatory activities by inhibiting the NF-κB pathway in various cancer types. About 750 natural and synthetic inhibitors of the NF-κB have been reported. These inhibitors include microbial and viral proteins, small RNA/DNA, antioxidants, small molecules, peptides, and engineered constitutively active polypeptides, all of which may inhibit canonical and alternative NF-κB pathways. Thus, blocking or targeting the NF-κB-signaling pathways using natural and synthetic compounds could be a potential mechanism to cure the NF-κB induced tumors.