Coinfection with pathogens that cause acute febrile illness (AFI) can complicate patient diagnosis and management. This report describes a fatal case of Leptospira spp./Zika virus (ZIKV) coinfection in Puerto Rico. The patient presented with a 5-day history of AFI; reported behavioral risk factors for leptospirosis; was diagnosed with possible leptospirosis, dengue, chikungunya, or ZIKV disease; and received appropriate treatment for leptospirosis and dengue. Following a 3-day hospitalization, the patient died due to acute gastrointestinal hemorrhage, and kidney and liver failure. Serologic diagnostic testing for leptospirosis and ZIKV disease was negative; however, molecular diagnostic testing performed postmortem was positive for detection of Leptospira spp. and ZIKV nucleic acid. This case demonstrates the need for continued clinical awareness of leptospirosis in areas experiencing outbreaks of pathogens that cause AFI and the need for evaluation of coinfection with AFI-causing pathogens as a risk factor for increased severity of disease.