The NLRP3 inflammasome may contribute to infarct development during acute cardiac ischemia-reperfusion (IR). Because infarct size strongly correlates with the degree of heart failure in the long term, therapies that reduce reperfusion injury are still needed as first primary care against heart failure development. Inhibition of the NLRP3 inflammasome is currently viewed as such a potential therapy. However, previous research studies directed at inhibition of various inflammatory pathways in acute cardiac IR injury were often disappointing. This is because inflammation is a double-edged sword, detrimental when hyperactive, but beneficial at lower activity, with activity critically dependent on time of reperfusion and cellular location. Moreover, several inflammatory mediators can also mediate cardioprotective signaling. It is reasonable that this also applies to the NLRP3 inflammasome, although current literature has mainly focused on its detrimental effects in the context of acute cardiac IR. Therefore, in this review, we focus on beneficial, cardioprotective properties of the NLRP3 inflammasome and its components NLRP3, ASC, and caspase-1. The results show that (1) NLRP3 deficiency prevents cardioprotection in isolated heart by ischemic preconditioning and in vivo heart by TLR2 activation, associated with impaired STAT3 or Akt signaling, respectively; (2) ASC deficiency also prevents in vivo TLR2-mediated protection; and (3) caspase-1 inhibition results in decreased infarction but impaired protection through the Akt pathway during mild ischemic insults. In conclusion, the NLRP3 inflammasome is not only detrimental, it can also be involved in cardioprotective signaling, thus fueling the future challenge to acquire a full understanding of NLRP3 inflammasome role in cardiac IR before embarking on clinical trials using NLRP3 inhibitors.