In the 2018 yellow fever (YF) outbreak in Brazil, we generated new transcriptomic data and combined it with clinical and immunological data to decode the pathogenesis of YF. Analyzing 79 patients, we found distinct gene expression patterns between acute YF, other viral infections, and the milder YF-17D vaccine infection. We identified a critical role for low-density, immature neutrophils in severe outcomes, marked by the downregulation of genes essential for neutrophil migration and maturation, such as PADI4, CSF3R, and ICAM1, in deceased patients. Our study also revealed complex interactions among inflammation-related genes, including increased CXCL10 and IL1R2 expression and decreased IL-1b expression in the acute phase. The diminished expression of HLA class II genes indicates impaired antigen presentation. These findings highlight the delicate balance of immune responses in YF pathogenesis and lay the groundwork for future therapeutic and diagnostic advancements.