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Toll-like receptors (TLR) are one among the initial responders of the immune system which participate in the activation inflammatory processes. Several different types of TLR such as TLR2, TLR4, TLR7 and TLR9 have been identified in various cell types, each having distinct ligands like lipids, lipoproteins, nucleic acids and proteins. Though its prime concern is xenobiotic defences, TLR signalling has also recognized as an activator of inflammation and associated development of chronic degenerative disorders (CDDs) including obesity, type 2 diabetes mellitus (T2DM), fatty liver disease, cardiovascular and neurodegenerative disorders as well as various types of cancers. Numerous drugs are in use to prevent these disorders, which specifically inhibit different pathways associated with the development of CDDs. Compared to these drug targets, inhibition of TLR, which specifically responsible for the inflammatory insults has proven to be a better drug target. Several natural products have emerged as inhibitors of CDDs, which specifically targets TLR signalling, among these, many are in the clinical trials. This review is intended to summarize the recent progress on TLR association with CDDs and to list possible use of natural products, their combinations and their synthetic derivative in the prevention of TLR-driven CDD development.