Enterovirus A71 (EV-A71) is a major cause of hand-foot-and-mouth disease (HFMD), particularly in cases that involve complications affecting the nervous system or cardiopulmonary function. In South America, EV-A71 has primarily been identified through studies of acute flaccid paralysis (AFP) and other neurological disorders. In September 2022, two children from a small city in Uruguay were hospitalized with presumptive rhombencephalitis, exhibiting symptoms of HFMD. EV-A71 was identified through RT-PCR and next-generation sequencing of stool and skin lesion samples. A maximum-likelihood phylogenetic analysis of the P1 coding region classified the Uruguayan strains as part of an emerging lineage, primarily reported in Europe over the past decade, known as the C1-like lineage. The findings presented here represent the first detection of the EV-A71 C1-like lineage in cases of HFMD and encephalitis reported from South America, underscoring the urgent need to enhance surveillance for HFMD, aseptic meningitis, encephalitis, and AFP, in countries facing challenges in establishing effective surveillance programs related to enteroviruses and associated diseases.