Non‐typhoidal Salmonella (NTS) are a significant source of foodborne illness worldwide, with disease symptoms most often presenting as self‐limiting gastroenteritis; however, occasionally the infection spreads and becomes invasive, frequently requiring anti‐microbial treatment. The cattle‐adapted Dublin serovar of NTS has commonly been associated with invasive illness and anti‐microbial resistance (AMR). Here, the enhanced resolution conferred by whole‐genome sequencing was utilized to elucidate and compare the resistome and genetic relatedness of 14 multidrug‐resistant (MDR) and one pan‐susceptible S. Dublin, isolated primarily in Pennsylvania, from fresh retail meat (one isolate) and humans (14 isolates). Twelve different genetic AMR determinants, including both acquired and chromosomal, were identified. Furthermore, comparative plasmid analysis indicated that AMR was primarily conferred by a putative IncA/C2 plasmid. A single pan‐susceptible S. Dublin isolate, collected from the same timeframe and geographical region as the MDR isolates, did not carry an IncA/C2 replicon sequence within its genome. Moreover, the pan‐susceptible isolate was genetically distinct from its MDR counterparts, as it was separated by ≥267 single nucleotide polymorphisms (SNPs), whereas there was a ≤38 SNP distance between the MDR isolates. Collectively, this data set advances our understanding of the genetic basis of the highly drug‐resistant nature of S. Dublin, a serovar with significant public health implications. [ABSTRACT FROM AUTHOR]