Since its initial emergence in Wuhan, China, the novel coronavirus (CoV) disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly grown into a pandemic. Most often, the morbidity and mortality linked to SARS-CoV-2 infection are brought on by the host's excessive and unchecked immunological response, characterised by a ‘cytokine storm’, which is mounted to fight the virus. The underlying cause of severe sequelae, including acute respiratory distress syndrome and multi-organ dysfunction in late-stage COVID-19 patients, is now understood to be the ‘cytokine storm’. SARS-CoV-2 is known to be extremely effective in causing inflammation through the inflammasome, a molecular sensor. Recent clinical trials have demonstrated mild clinical recovery in COVID-19 patients therapeutically treated with inflammasome inhibitors. We used K18-hACE2 mice to test a number of inflammasome-blocking medications, including belnacasan, MCC950, oridonin, and tranilast, as potential preventive candidates to reduce the clinical severity of SARS-CoV-2. Inflammasome inhibitors were prophylactically given to SARS-CoV-2-infected mice, and the percentage weight changes, clinical score, and survival curve analysis, as well as the gross and histological evaluation of the mice's lung tissues, suggested mild to moderate clinical improvement. However, these drugs could not inhibit the replication, propagation, and dissemination of SARS-CoV-2 in a mouse model of infection. These NLRP3 inflammasome inhibitors might be more effective when used as adjuvant therapy for COVID-19 patients together with antivirals, supportive care, and other conventional therapeutic approaches.