ABSTRACT International travelers are frequently afflicted by acute infectious diarrhea, commonly referred to as travelers’ diarrhea (TD). Antibiotics are often prescribed as treatment or prophylaxis for TD; however, little is known about the impacts of these regimens on travelers’ gut microbiomes and carriage of antibiotic resistance genes (ARGs). Here, we analyzed two cohorts totaling 153 US and UK servicemembers deployed to Honduras or Kenya. These subjects either experienced TD during deployment and received a single dose of one of three antibiotics [Trial Evaluating Ambulatory Therapy of Travelers’ Diarrhea (TrEAT TD) cohort] or took once-daily rifaximin (RIF), twice-daily RIF, or placebo as prophylaxis to prevent TD [Trial Evaluating Chemoprophylaxis Against Travelers’ Diarrhea (PREVENT TD) cohort]. We applied metagenomic sequencing on 340 longitudinally collected stool samples and whole-genome sequencing on 54 Escherichia coli isolates. We found that gut microbiome taxonomic diversity remained stable across the length of study for most treatment groups, but twice-daily RIF prophylaxis significantly decreased microbiome richness post-travel. Similarly, ARG diversity and abundance were generally stable, with the exception of a significant increase for the twice-daily RIF prophylaxis group. We also did not identify significant differences between the ARG abundance of E. coli isolates from the TrEAT TD cohort collected from different treatment groups or timepoints. Overall, we found no significant worsening of gut microbiome diversity or an increase in ARG abundance following single-dose treatment for TD, underscoring that these can be effective with low risk of impact on the microbiome and resistome, and identified the relative microbiome risks and benefits associated with the three regimens for preventing TD. IMPORTANCE The travelers’ gut microbiome is potentially assaulted by acute and chronic perturbations (e.g., diarrhea, antibiotic use, and different environments). Prior studies of the impact of travel and travelers’ diarrhea (TD) on the microbiome have not directly compared antibiotic regimens, and studies of different antibiotic regimens have not considered travelers’ microbiomes. This gap is important to be addressed as the use of antibiotics to treat or prevent TD—even in moderate to severe cases or in regions with high infectious disease burden—is controversial based on the concerns for unintended consequences to the gut microbiome and antimicrobial resistance (AMR) emergence. Our study addresses this by evaluating the impact of defined antibiotic regimens (single-dose treatment or daily prophylaxis) on the gut microbiome and resistomes of deployed servicemembers, using samples collected during clinical trials. Our findings indicate that the antibiotic treatment regimens that were studied generally do not lead to adverse effects on the gut microbiome and resistome and identify the relative risks associated with prophylaxis. These results can be used to inform therapeutic guidelines for the prevention and treatment of TD and make progress toward using microbiome information in personalized medical care.