COVID-19 can present with lymphopenia and extraordinary complex multi-organ pathologies that can trigger long-term sequela. Given that inflammasome products, like caspase-1, play a role in the pathophysiology of a number of co-morbid conditions, we investigated caspases across the spectrum of COVID-19 disease. We assessed transcriptional states of multiple caspases and using flow cytometry, the expression of active caspase-1 in blood cells from COVID-19 patients in acute and convalescent stages of disease. Non-COVID-19 subjects presenting with various co-morbid conditions served as controls. Single-cell RNA-seq data of immune cells from COVID-19 patients showed a distinct caspase expression pattern in T cells, neutrophils, dendritic cells and eosinophils compared to controls. Caspase-1 was upregulated in CD4+ T-cells from hospitalized COVID-19 patients compared to unexposed controls. Post-COVID-19 patients with lingering symptoms (long-haulers) also showed up-regulated caspase-1 activity in CD4+ T-cells that ex vivo was attenuated with a select pan-caspase inhibitor. We observed elevated caspase-3/7 levels in red blood cells from COVID-19 patients compared to controls that was reduced following caspase inhibition. Our preliminary results suggest an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Further clinical correlations of caspase expression in different stages of COVID-19 will be needed. Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate or prevent severe COVID-19.