Abstract Background International travelers are often prescribed antibiotics for self-treatment of travelers’ diarrhea (TD), but the benefits and risks of antibiotics are debated. We assessed the prescribing patterns of empiric antibiotics for TD in international travelers evaluated at Global TravEpiNet (GTEN) sites (2009–2018). Methods We performed a prospective, multisite cross-sectional study regarding antibiotic prescriptions for the self-treatment of TD at 31 GTEN sites providing pretravel consultations to adult international travelers. We described traveler demographics, itineraries, and antibiotic(s) prescribed. We used multivariable logistic regressions to assess the association of year of consultation with antibiotic prescribing (yes/no) and class (fluoroquinolones vs azithromycin). We performed interrupted time-series analyses to examine differences in prescribing before and after the Food and Drug Administration (FDA) warning on fluoroquinolones (July 2016). Results Antibiotics were not prescribed in 23 096 (22.2%) of 103 843 eligible pretravel GTEN consultations; azithromycin and fluoroquinolones were most frequently prescribed. Antibiotic prescribing declined significantly each year between 2009 and 2018 (odds ratio [OR], 0.84; 95% CI, 0.79–0.89), as did fluoroquinolone prescribing, relative to azithromycin (OR, 0.77; 95% CI, 0.73–0.82). The rate of decline in fluoroquinolone prescribing was significantly greater after the FDA fluoroquinolone warning (15.3%/year) than before (1.1%/year; P < .001). Conclusions Empiric antibiotics for TD were prescribed in >75% of pretravel GTEN consultations, but antibiotic prescribing declined steadily between 2009 and 2018. Fluoroquinolones were less frequently prescribed than azithromycin, especially after the 2016 FDA fluoroquinolone warning. Emphasis on the risks of antibiotics may influence antibiotic prescribing by providers for empiric treatment of TD.