Our objective was to conduct a systematic review of the quality of previous publications that evaluated the efficacy of antimicrobials for the treatment of bovine respiratory disease (BRD) in calves. The literature search strategy, based on population, intervention, and outcome of studies written in English from CabDirect, PubMed, Web of Science and Scopus, was conducted on December 2018; a total of 2,058 publications were retrieved. Publications of interest were clinical trials and experimental challenges that used antimicrobials to treat BRD in calves <6 mo. Thirty-four manuscripts containing 37 trials were retained after screening the titles (n = 901), the abstracts (n = 308) and the full papers. The selected trials included clinical trials (n = 22) and challenge trials (n = 15) that dated back from 1979. The median number of animals enrolled was 49 and ranged from 11 to 696 calves. Seventeen manuscripts were either funded or had authors affiliated with pharmaceutical companies. A total of 29 trials were randomized but only 14 of those were blinded. Fifteen trials included a negative control treatment; but only 6 were randomized and blinded. Trials with negative control evaluated the efficacy of: one (n = 3) or more (n = 2) antimicrobials, anti-inflammatories combined with antimicrobials (n = 2), various dosages or timing of treatments (n = 7), or combination of antimicrobial treatments (n = 1). Macrolides were the most common antimicrobial class evaluated (n = 14). The length of the observational period for health outcomes ranged from 3 d to 8 wks. Fever was the most frequent clinical sign of BRD evaluated (n = 26). Only 8 trials evaluated clinical signs of respiratory disease using a scoring tool. In addition to clinical signs, 13 trials performed pathological examination of euthanized calves. Although considerable numbers of studies have been conducted on antimicrobial use for BRD in calves, very few studies were controlled and randomized. Future research on BRD should follow standardized methods for the evaluation of clinical outcomes. Funding provided by CDFA–AUS project.