Background: While enteroviruses (EVs) are recognized causes of diverse illnesses, little is known about the epidemiology and molecular characteristics of uncommon enterovirus C (EV-C) types, including EV-C104, EV-C105, and EV-C109. Methods: We conducted genomic surveillance of EVs at the Johns Hopkins Health System between 2018 and 2024 (a total of 3715 samples), identifying EV-C104, EV-C105, and EV-C109 in respiratory samples. VP4-VP2 and whole-genome sequencing were used to assess genetic diversity and intra-host evolution. Results: Five EV-C105 infections were identified primarily in pediatric patients, presenting with a range of clinical features including fever, gastrointestinal symptoms, and cerebellitis. Prolonged EV-C104 and EV-C109 infections were identified in two immunocompromised adults. EV-C104 persisted for over five months and showed evidence of viral genomic changes (intra-host evolution). EV-C109 was detected over a four-month period. Phylogenetic analysis revealed a novel EV-C105 clade (C3) closely related to recent USA strains. EV-C104 genomes aligned with genotype B sequences from the USA and Europe, while EV-C109 sequences were similar to 2014–2015 strains from the Netherlands. Conclusions: These findings highlight the emergence, persistence, and genetic evolution of uncommon EV-C types in Maryland, especially among immunocompromised hosts, emphasizing the importance of continued genomic surveillance and clinical correlations.