Inflammasome activation is one of the first steps in initiating innate immune responses. In this work, we studied the activation of inflammasomes in the airways of critically ill COVID-19 patients and the effects of N-acetylcysteine (NAC) on inflammasomes. Tracheal biopsies were obtained from critically ill patients without COVID-19 and no respiratory disease (control, n = 32), SARS-CoV-2 B.1 variant (n = 31), and B.1.1.7 VOC alpha variant (n = 20) patients. Gene expression and protein expression were measured by RT-qPCR and immunohistochemistry. Macrophages and bronchial epithelial cells were stimulated with different S, E, M, and N SARS-CoV-2 recombinant proteins in the presence or absence of NAC. NLRP3 inflammasome complex was over-expressed and activated in the COVID-19 B.1.1.7 VOC variant and associated with systemic inflammation and 28-day mortality. TLR2/MyD88 and redox NOX4/Nrf2 ratio were also over-expressed in the COVID-19 B.1.1.7 VOC variant. The combination of S-E-M SARS-CoV-2 recombinant proteins increased cytokine release in macrophages and bronchial epithelial cells through the activation of TLR2. NAC inhibited SARS-CoV-2 mosaic (S-E-M)-induced cytokine release and inflammasome activation. In summary, inflammasome is over-activated in severe COVID-19 and increased in B.1.1.7 VOC variant. In addition, NAC can reduce inflammasome activation induced by SARS-CoV-2 in vitro, which may be of potential translational value in COVID-19 patients.