Lyme disease (LD) is the most common tick-borne illness across the United States, caused by the bacteriumBorrelia burgdorferi sensu latoand transmitted to humans by the bite of infectedIxodesticks. Jamestown Canyon Virus (JCV) is an emerging mosquito-borne pathogen found mostly in the upper Midwest and Northeastern United States. Co-infection between these two pathogens has not been previously reported since it would require the host to be bitten by the two infected vectors at the same time. We report a 36-year-old man who presented with erythema migrans and meningitis. While erythema migrans is a pathognomonic sign of early localized Lyme disease, Lyme meningitis does not occur in this stage but in the early disseminated stage. Furthermore, CSF tests were not supportive of neuroborreliosis, and the patient was ultimately diagnosed with JCV meningitis. We review JCV infection, LD, and this first reported co-infection to illustrate the complex interaction between different vectors and pathogens and to emphasize the importance of considering co-infection in people who live in vector-endemic areas.