Mitochondrial, BCL-2 family regulated, apoptosis plays a vital role in human health by promoting the safe clearance of damaged and infected cells by the innate immune system. However, our recent work has revolutionised this area by showing that activation of the mitochondrial effectors BAX and BAK, upon targeting pro-survival MCL-1 and BCL-XL, in LPS-primed macrophages can induce a complex series of events that culminate in NLRP3 inflammasome and IL-1β activation. Intriguingly, we found that LPS signalling delayed apoptosis, and postulated that the short-lived LPS-inducible pro-survival protein BCL2A1 might limit BAX/BAK activation. In line with this concept, we discovered that genetic deletion of BCL2A1 renders macrophages sensitive to rapid killing and IL1β secretion upon loss of MCL1 and BCLxL activity. Even more remarkably, we found that in LPS-primed monocytes, loss of MCL-1 and A1 was sufficient for apoptosis and activation of IL-1β. In short, our data highlights that BCL2A1 protein may guard myeloid cells against death and inflammation during Gram-negative bacterial infections. Moreover, it highlights the need to further define how BCL2A1 protein is regulated during infection and its physiological significance during life-threatening infections, where repurposing anti-cancer BCL-2 family targeting drugs may represent an attractive approach to combat antimicrobial resistance.