Antibiotics constitute a major class among drugs commonly prescribed either empirically or for microbiologically documented infections in clinical practice. In addition, due to medical necessity physicians are forced, at times, to prescribe medications for off-label indications. The authors sought to record the frequency of the off-label use of antibiotics among both adult and pediatric patients. PubMed and Scopus databases were searched to identify relevant studies. A total of 25 studies met the inclusion criteria (725,124,505 prescriptions); 16 were prospective and nine retrospective. Fifteen studies reported on the pediatric population, seven on adults who had received a specific antibiotic, two on adult critical-care patients, and one on the general outpatient population. In the pediatric population, the percentage of off-label prescriptions varied from 1 to 94%. Off-label prescriptions varied from 19 to 43% in adult critical-care patients. Last, one study reporting on general outpatient care showed that 23% of prescriptions were off-label. Antibiotics are frequently prescribed as off-label among patient populations. The wide variation observed in the off-label use of antibiotics among pediatric patients might be attributed to the heterogeneity among the study populations regarding the age of children. Although this unapproved manner of prescribing cannot always be avoided, clinicians should only use unapproved drugs in cases when there are no effective alternatives are available and based on scientific evidence regarding safety and effectiveness.