In May 2024, the Brazilian state of Rio Grande do Sul experienced an historic flood that affected millions of people. Hundreds of thousands of people were displaced by the record-breaking flood waters, exposing them to water-borne pathogens, including leptospirosis. With concern for an outbreak, local efforts focused on identifying and treating any potential cases of leptospirosis. Using data from a local database for people presenting with signs and symptoms compatible with leptospirosis, we conducted a retrospective-prospective cohort study to estimate the incidence of confirmed cases. Of 539 patients reported to the database, a total of 485 patients were tested for leptospirosis and 303 were tested for Dengue (with 283 testing for both pathogens). We found 17 (3.5%) confirmed cases of leptospirosis and 102 (33.7%) confirmed cases of dengue fever. Most tested negative for both, with several confirmed cases of Hantavirus, Influenza A, and HIV. Although there were no significant differences between diagnoses and exposure risk factors, we did find several clinical differences, including headache, respiratory symptoms, diarrhea, acute kidney injury, jaundice, bleeding diathesis, and pulmonary hemorrhage. Leptospirosis was also found to be significantly associated with adverse clinical outcomes when compared to both dengue and the Unrelated/Unknown illness group and more likely to be of the male sex. These data reinforce the need for broader systematic surveillance for pathogens that may circulate in the event of major environmental disasters. Further, stronger diagnostics are urgently needed to distinguish between the causes of largely febrile outbreak in the face of a changing climate.