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The ubiquitous bacterial pathogen is the causative agent of both enteric fever and gastroenteritis. Despite its significant global health burden, we lack an understanding of its genetic diversity during acute infection, with ramifications for treatment and prevention. Here, we investigated within-host infection diversity of acute salmonellosis using whole-genome sequencing of blood or stool isolates obtained from 23 different patients. We found that intestinal infections exhibited greater genetic variation than blood infections, including in their plasmid content. While same-patient isolates were separated by 10 single nucleotide polymorphisms or less, they often differed in the carriage of genes or alleles, including those associated with antibiotic resistance or virulence. Given the longstanding emphasis on single colony isolation in clinical and laboratory microbiology, these findings have implications for how we both study evolution and transmission and how we treat salmonellosis in an age of increasing antibiotic resistance.