Neonatal calf diarrhea (NCD) is a major cause of death and economic loss in the cattle industry. Although NCD is caused by a variety of nutritional factors and non-bacterial pathogens, treatment typically includes systemic antimicrobial therapy, even for non-severe cases that are more likely to have non-bacterial causes. Novel, non-antimicrobial therapies are needed to reduce antimicrobial use and optimize production efficiency.This production-level study compared the efficacy of activated charcoal to that of an antimicrobial regimen for treating mild-to-moderate cases of NCD, and identified the most common etiological agents. Calves diagnosed with non-severe diarrhea were randomly allocated into 3 treatment groups (n = 86 per group): group A received a standard antimicrobial regimen, B received both antimicrobials and activated charcoal, and C received activated charcoal only. Animals were monitored over the course of 7 days for mortality and recovery from diarrhea. Fecal samples were collected upon enrollment (day 0) and on day 7 to assess the presence of major NCD-causing pathogens.Mortality was higher for groups B and C relative to A, although this difference was only statistically significant for group B vs A. No significant difference in the number of recovered animals was observed among the treatment groups, although group C was significantly slower to recover than A or B. The vast majority of day 0 samples were positive for non-bacterial organisms (mainly rotavirus and Cryptosporidium parvum), which decreased significantly by day 7 regardless of treatment group.Antimicrobials only moderately improved outcomes for non-severe diarrhea cases relative to activated charcoal. Thus, systemic antimicrobial treatment is likely unnecessary for the majority of NCD cases and should be limited to severe cases.