Salmonella enterica serovar Infantis (S. Infantis) is an emerging zoonotic foodborne pathogen. This study used publicly available data on S. Infantis from the National Antimicrobial Resistance Monitoring System (NARMS) to evaluate the prevalence and antimicrobial resistance (AMR) of S. Infantis across the United States of America between 2013 and 2020. The highest prevalence of S. Infantis was identified in chickens (3027 isolated from 18,078 samples
16.75 %), swine (431/5600
6.09 %), turkeys (161/4019
4.01 %), humans (737/18,774
3.93 %), and cattle (134/8010
1.67 %). Over the study period, a significant increase in S. Infantis isolates of chickens and turkeys, a moderate in cattle, a low in humans, and no increase in swine was observed. High resistance to tetracycline, nalidixic acid, and sulfisoxazole and low resistance to cefoxitin and amoxicillin-clavulanic acid were detected among livestock, poultry, and human isolates. Reduced susceptibility to ciprofloxacin was observed in 52.46 % of chicken isolates, 62.11 % of turkey, and 18.59 % of human isolates. Multi-drug resistance (MDR
resistant to at least one agent in ≥3 antimicrobial classes) was detected in 93 % of turkeys, 83 % of chickens, 22 % of humans, 16 % of cattle, and 6 % of swine isolates. This study identified differences in the prevalence and AMR of S. Infantis across the food chain, highlighting the importance of a focused One Health approach to mitigate the emergence of AMR and to reduce the health burden of infections with drug-resistant isolates.