Abstract: <jats:sec> <jats:title>Background:</jats:title> <jats:p> Inflammation is the fast coordinating response of body’s immune system to irritants caused by pathogens, external injuries and chemical or radiation effects. The NLRP3 (nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome is a critical component of the innate immune system. Malfunction of NLRP3 inflammasome will contribute to various pathogenesis of complex diseases, such as uncontrolled infection, autoimmune diseases, neurodegenerative diseases, and metabolic disorders. This review aims to describe recent progress on discovery of NLRP3 inflammasome inhibitors and their therapeutic potential. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p> Based on the mechanism of NLRP3 activation, several types of NLRP3 inhibitors were described and summarized according to their origins, structures, bioactivity and mechanism of action. Structure-activity-relationship (SAR) was also listed for different scaffolds, as well as effective pharmacophore. </jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>Over one-hundred papers were included in the review. The development of NLRP3 inhibitors was described from the earliest glyburide in 2001 to the latest progress in 2019. Several series of inhibitors were categorized, such as JC-series based on glyburide and BC-series based on 2APB. Many other small molecules as NLRP3 inhibitors were also listed. SAR, application in related therapeutic models and five different action mechanisms were described. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p> The findings of this review confirmed the importance of developing NLRP3 inflammasome inhibitors. Various NLRP3 inhibitors have been discovered as effective therapeutic treatments to multiples diseases such as type II diabetes, experimental autoimmune encephalomyelitis, stress-related mood disorders, etc. The development of a full range of NLRP3 inflammasome inhibitors is still at its foundational phase. We are looking forward to identification of inhibitory agents which provide the most potent therapeutic strategies and efficiently treat NLRP3 inflammasome-related inflammatory diseases. </jats:p> </jats:sec>