NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) receptor serves as the central node of immune sensing in the innate immune system, and plays an important role in the initiation and progression of chronic diseases. Cryo-electron microscopy (cryo-EM) has provided insights into the conformation of various oligomers within the NLRP3 activation pathway, significantly advancing our understanding of the mechanisms underlying NLRP3 inflammasome activation. Despite the extensive network of protein-protein interactions (PPIs) involved in the assembly and activation of NLRP3 inflammasome, the utilization of protein-protein interactions has been relatively overlooked in the development of NLRP3 inhibitors. This review focuses on summarizing PPIs within the NLRP3 inflammasome activation pathway and small molecule inhibitors capable of interfering with PPIs to counteract the NLRP3 overactivation. Small molecule NLRP3 inhibitors have been gained significant attention owing to their remarkable efficacy, excellent safety profiles, and unique mechanisms of action.