Yellow fever (YF) remains a public health problem despite the availability of a highly effective vaccine. In 2018, an outbreak occurred in the Brazilian state of São Paulo, where YF virus (YFV) vaccination was not mandatory, resulting in 504 confirmed cases with a 35% case-fatality. It has been hypothesized that immune responses generated following vaccination with the attenuated virus or infection with wild-type YFV are similar, but studies detailing immunopathogenesis after natural YFV infection are scarce. In this study, we aimed to characterize the expansion kinetics of antibody-secreting cells (ASC) in patients with YF and investigate the immune cell changes in spleen microscopies of individuals who died after YFV infection. We collected blood samples from 70 patients with YF at up to six timepoints during the acute and convalescent phases, and spleen specimens were collected from 24 individuals who died and underwent necropsies. Flow cytometry analysis revealed that the frequency of circulating ASC (CD20^-/CD27^high/CD38^high), particularly plasmablasts (CD138^-), was significantly higher in individuals who died, peaking on the 6th day after symptom onset (p = 0.0013). Higher frequency of circulating plasma cells (CD138⁺) was detected in deceased individuals compared to survivors at 10 days after symptom onset (p = 0.0026). Spleen specimens were processed for immunohistochemistry and showed a clear disarrangement of the spleen white pulp, with a decreased cell count per mm² for cells expressing CD3, CD10, CD20, CD23, CD68, FOXP3, CXCR5 and CD138, and an increased count of cells expressing CD39, CXCR4 and IgG, when compared to a group of non-infected patients who underwent post-trauma splenectomy. Taken together, our data provide novel insights into the immunopathogenesis of YFV infection, suggesting an imbalanced immune response in individuals who died of the disease.