The optimum antibiotic treatment for cellulitis and erysipelas lacks consensus. The available trial data do not demonstrate the superiority of any agent, and data are limited on the most appropriate route of administration or duration of therapy. To assess the efficacy and safety of antibiotic therapy for non-surgically acquired cellulitis. The following databases were searched to June 28, 2016: Cochrane Central Register of Controlled Trials (2016, issue 5), Medline (from 1946), Embase (from 1974), and Latin American and Caribbean Health Sciences Information System (LILACS) (from 1982). In addition, 5 trials databases and the reference lists of included studies were searched. Further searches of PubMed and Google Scholar were undertaken from June 28, 2016, to December 31, 2018. Randomized clinical trials comparing different antibiotics, routes of administration, and treatment durations were included. For data collection and analysis, the standard methodological procedures of the Cochrane Collaboration were used. For dichotomous outcomes, the risk ratio and its 95% CI were calculated. A summary of findings table was created for the primary end points, adopting the GRADE approach to assess the quality of the evidence. The primary outcome was the proportion of patients cured, improved, recovered, or symptom-free or symptom-reduced at the end of treatment, as reported by the trial. The secondary outcome was any adverse event. A total of 43 studies with a total of 5999 evaluable participants, whose age ranged from 1 month to 96 years, were included. Cellulitis was the primary diagnosis in only 15 studies (35%), and in other studies the median (interquartile range) proportion of patients with cellulitis was 29.7% (22.9%-50.3%). Overall, no evidence was found to support the superiority of any 1 antibiotic over another, and antibiotics with activity against methicillin-resistant Staphylococcus aureus did not add an advantage. Use of intravenous antibiotics over oral antibiotics and treatment duration of longer than 5 days were not supported by evidence. In this systematic review and meta-analysis, only low-quality evidence was found for the most appropriate agent, route of administration, and duration of treatment for patients with cellulitis; future trials need to use a standardized set of outcomes, including severity scoring, dosing, and duration of therapy.