The objective of this study was to conduct a systematic review of the scientific literature evaluating the efficacy and comparative efficacy of antimicrobials (AMs) for the treatment of diarrhea in calves. Eligible studies were non- and randomized controlled trials evaluating an AM intervention against a positive and negative control, with at least one of the following outcomes: fecal consistency score, fever, dehydration, appetite, attitude, weight gain, and mortality. Four electronic databases were searched. Titles and abstracts (three reviewers) and full texts (two reviewers) were screened. A total of 2899 studies were retrieved; 11 studies met the inclusion criteria. The risk of bias was assessed. Most studies had incomplete reporting of trial design and results. Eight studies compared AMs to a negative control (placebo or no treatment). Among eligible studies, the most common outcomes reported were diarrhea severity (n = 6) and mortality (n = 6). Eligible studies evaluated very different interventions and outcomes; thus, a meta-analysis was not performed. The risk of bias assessment revealed concerns with reporting of key trial features, including disease and outcome definitions. Insufficient evidence is available in the scientific literature to assess the efficacy of AMs in treating calf diarrhea.