Inflammation plays a pivotal role in the ischemia/reperfusion (I/R) injury. Inflammatory response is initiated by the detection of pathogen-associated molecular patterns and/or damage-associated molecular patterns via extracellular and intracellular pattern recognition receptors. The nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing protein 3 (NLRP3) is a component of pattern recognition receptors and serves a vital role in inflammatory response by forming an intracellular multi-protein complex known as NLRP3 inflammasome. There is increasing evidence that NLRP3 inflammasome acts as guardians against host-derived danger materials. The inappropriate activation of NLRP3 contributes to the progression of I/R injury such as myocardial, cerebral, renal, hepatic and retinal I/R injuries. In this review, we summarize the role of NLRP3 in inflammatory response and discuss the relationship between NLRP3 and I/R injury. We also provide insights into new treatment strategies for targeting NLRP3 inflammasome, as well as the upstream and downstream components of NLRP3 in alleviating I/R injury.