Diseases associated with unhealthy diets and lifestyles, such as type 2 diabetes, atherosclerosis, and fatty liver disease, are driven by sterile tissue inflammation that is driven in part by the NLRP3 inflammasome. This macromolecular complex responds to diverse danger signals by inducing secretion of inflammatory IL-1 family cytokines and promoting a type of cell death called pyroptosis. Saturated fatty acids (SFAs) are known to activate the NLRP3 inflammasome but the intracellular pathways by which this activation occurs are incompletely described. I hypothesized that SFAs activate the NLRP3 inflammasome through different intracellular pathways than “classical” NLRP3 activators. Motivated by preliminary data on the kinetics of NLRP3 activation by the SFA palmitic acid (PA) and the weak effect of the NLRP3 inhibitor MCC950, I found that this process requires not only the canonical inflammasome pathway but also the non-canonical inflammasome components caspase-4/5/11. Disruption of either pathway leads to partial impairments in the inflammasome response to PA, though the canonical pathway generally accounts for more IL-1 secretion while the non-canonical pathway is the primary driver of cell death. PA also has a weaker dependence on reactive oxygen species (ROS) compared to other NLRP3 activators. While classical activators engage multiple ROS sources including both mitochondrial and cytosolic enzymes, PA activation of NLRP3 specifically requires ROS from NADPH oxidases. PA exposure leads to activation of the MAP kinase JNK in the cytosol of macrophages and interference with JNK signaling blocks PA-induced NLRP3 activation. While SFAs activate the NLRP3 inflammasome, unsaturated fatty acids such as arachidonic acid (AA) inhibit NLRP3 activation. AA counteracts the effect of PA on multiple intracellular signaling pathways, especially the JNK pathway. My findings further characterize the mechanisms by which SFAs activate the NLRP3 inflammasome and describe a novel role of JNK as a key mediator for opposing effects of saturated and unsaturated fatty acids on NLRP3. These mechanistic insights highlight pathways that may be targeted to delay or reverse the progression of sterile inflammation in many “lifestyle diseases”.