The innate immune system is tightly regulated by a complex network of chemical signals triggered by pathogens, cellular damage, and environmental stimuli. While it is well-established that changes in the extracellular environment can significantly influence the immune response to pathogens and damage-associated molecules, there remains a limited understanding of how changes in environmental stimuli specifically impact the activation of the NLRP3 inflammasome, a key component of innate immunity. Here, we demonstrated how shear stress can act as Signal 2 in the NLRP3 inflammasome activation pathway by treating LPS-primed immortalized bone marrow-derived macrophages (iBMDMs) with several physiologically relevant magnitudes of shear stress to induce inflammasome activation. We demonstrated that magnitudes of shear stress within 1.0 to 50 dyn/cm were able to induce ASC speck formation, while 50 dyn/cm was sufficient to induce significant calcium signaling, gasdermin-D cleavage, caspase-1 activity, and IL-1β secretion, all hallmarks of inflammasome activation. Utilizing NLRP3 and caspase-1 knockout iBMDMs, we demonstrated that the NLRP3 inflammasome was primarily activated as a result of shear stress exposure. Quantitative polymerase chain reaction (qPCR), ELISA, and a small molecule inhibitor study aided us in demonstrating that expression of Piezo1, NLRP3, gasdermin-D, IL-1β, and CCL2 secretion were all upregulated in iBMDMs treated with shear stress. This study provides a foundation for further understanding the interconnected pathogenesis of chronic inflammatory diseases and the ability of shear stress to play a role in their progression.