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Abstract Background Antibiotics are essential to treat for many childhood bacterial infections; however inappropriate antibiotic use contributes to antimicrobial resistance. For childhood diarrhea, empiric antibiotic use is recommended for dysentery (bloody diarrhea) for which first-line therapy is ciprofloxacin. We assessed inappropriate antibiotic prescription for childhood diarrhea in two primary healthcare facilities in Kenya. Methods We analyzed data from the Kenya Population Based Infectious Disease Surveillance system in Asembo (rural, malaria-endemic) and Kibera (urban slum, non-malaria-endemic). We examined records of children aged 2–59 months with diarrhea (≥3 loose stools in 24 h) presenting for care from August 21, 2009 to May 3, 2016, excluding visits with non-diarrheal indications for antibiotics. We examined the frequency of antibiotic over-prescription (antibiotic prescription for non-dysentery), under-prescription (no antibiotic prescription for dysentery), and inappropriate antibiotic selection (non-recommended antibiotic). We examined factors associated with over-prescription and under-prescription using multivariate logistic regression with generalized estimating equations. Results Of 2808 clinic visits with diarrhea in Asembo, 2685 (95.6%) were non-dysentery visits and antibiotic over-prescription occurred in 52.5%. Of 4697 clinic visits with diarrhea in Kibera, 4518 (96.2%) were non-dysentery and antibiotic over-prescription occurred in 20.0%. Antibiotic under-prescription was noted in 26.8 and 73.7% of dysentery cases in Asembo and Kibera, respectively. Ciprofloxacin was used for 11% of dysentery visits in Asembo and 0% in Kibera. Factors associated with over- and under-prescription varied by site. In Asembo a discharge diagnosis of gastroenteritis was associated with over-prescription (adjusted odds ratio [aOR]:8.23, 95% confidence interval [95%CI]: 3.68–18.4), while malaria diagnosis was negatively associated with antibiotic over-prescription (aOR 0.37, 95%CI: 0.25–0.54) but positively associated with antibiotic under-prescription (aOR: 1.82, 95%CI: 1.05–3.13). In Kibera, over-prescription was more common among visits with concurrent signs of respiratory infection (difficulty breathing; aOR: 3.97, 95%CI: 1.28–12.30, cough: aOR: 1.42, 95%CI: 1.06–1.90) and less common among children aged