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Salmonella enterica subsp. enterica serovar Newport ( S . Newport) is a clinically and epidemiologically significant serovar in the United States. It is the second most prevalent clinically isolated Salmonella serovar in the United States, and it can contaminate a wide variety of food products. In this study, we evaluated the population structure of S . Newport clinical isolates obtained by the Tennessee Department of Health during routine surveillance ( n  = 346), along with a diverse set of other global clinical isolates obtained from EnteroBase ( n  = 271). Most of these clinical isolates belonged to established lineages II and III. Additionally, we performed lineage-specific phylogenetic analyses and were able to identify 18 potential epidemiological clusters among the isolates from Tennessee, which represented a greater proportion of Tennessee isolates belonging to putative epidemiological clusters than the proportion of isolates of this serovar that are outbreak related. IMPORTANCE This study provides insight on the genomic diversity of one of the Salmonella serovars that most frequently cause human illness. Specifically, we explored the diversity of human clinical isolates from a localized region (Tennessee) and compared this level of diversity with the global context. Additionally, we showed that a greater proportion of isolates were associated with potential epidemiological clusters (based on genomic relatedness) than historical estimates. We also identified that one potential cluster was predicted to be multidrug resistant. Taken together, these findings provide insight on Salmonella enterica serovar Newport that can impact public health surveillance and responses and serve as a foundational context for the Salmonella research community.