Morbillivirus canis (canine distemper virus, CDV) remains a pathogen of major veterinary and conservation significance. Here, we summarize two decades of CDV surveillance in Uruguay by integrating laboratory-confirmed cases, diagnostic advances, molecular epidemiology, and neuropathological findings. Between 2006 and 2026, CDV infection was confirmed in 270 of 460 dogs submitted for diagnostic testing, supporting sustained transmission among clinically suspected cases. Confirmed infections were concentrated in young dogs and were more frequent during colder months, although the season was not significantly associated with diagnostic outcome. Dogs reported as vaccinated had a lower proportion of positive results than unvaccinated dogs; however, CDV infection was also detected in animals with reported vaccination history, suggesting that failures at some point in the immunization process cannot be ruled out and highlighting the need for improved records of vaccination protocols, immune status, and vaccine handling. Diagnostic capacity evolved from conventional RT-PCR to RT-qPCR, droplet digital PCR, and whole-genome sequencing, strengthening both clinical diagnosis and genomic surveillance. Phylogenetic analysis of the hemagglutinin gene showed that all Uruguayan strains characterized to date belong to the Europe/South America 1 lineage and revealed two locally differentiated clades, UY-I and UY-II, that co-circulated without clear temporal or geographic segregation in the available dataset. Comparative neuropathological analysis of fatal cases showed severe demyelinating lesions in both vaccinated and unvaccinated dogs, with no detectable differences in lesion pattern or stage in this limited series. These findings reveal sustained CDV transmission and local genetic structuring in Uruguay and support the need for continuous molecular and genomic surveillance, improved vaccination monitoring, and integrated One Health strategies to reduce the impact of CDV on domestic dogs and susceptible wildlife.