The regulation of the pleiotropic transcription factor, nuclear factor-κB (NF-κB) by miRNAs and proteins is extensively studied. More recently, the NF-κB signaling was also reported to be regulated by several long non-coding RNAs (lncRNAs) that constitute the major portion of the noncoding component of the human genome. The common NF-κB associated lncRNAs include NKILA, HOTAIR, MALAT1, ANRIL, Lethe, MIR31HG, and PACER. The lncRNA and NF-κB signaling crosstalk during cancer and other diseases such as cardiomyopathy, celiac disease, cerebral infarction, chronic kidney disease, diabetes mellitus, Kawasaki disease, pregnancy loss, and rheumatoid arthritis. Some NF-κB related lncRNAs can affect gene expression without modulating NF-κB signaling. Most of the lncRNAs with a potential to modulate NF-κB signaling are regulated by NF-κB itself suggesting a feedback regulation. The discovery of lncRNAs have provided a new type of regulation for the NF-κB signaling and thus could be explored for therapeutic interventions. The manner in which lncRNA and NF-κB crosstalk affects human pathophysiology is discussed in this review. The challenges associated with the therapeutic interventions of this crosstalk are also discussed.