OBJECTIVES: The aim of this study is to evaluate existing evidence on the effectiveness of amoxicillin and amoxicillin-clavulanate for community-acquired pneumonia in children and adults. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Cochrane Library, Web of Science and Ovid-MEDLINER were searched with no language restrictions through 16 July 2024. ELIGIBILITY CRITERIA: We included studies comparing the effectiveness of amoxicillin or amoxicillin-clavulanate versus other antibiotics or placebo. DATA EXTRACTION AND SYNTHESIS: Only randomised controlled trials comparing amoxicillin or amoxicillin-clavulanate with another antibiotic or placebo with a primary outcome of clinical resolution or clinical failure were eligible for our review. We used random-effects and fixed-effects logistic regression models to estimate the pooled treatment effect size. Heterogeneity of the studies was evaluated using the τ statistic. We performed an unplanned frequentist random-effects network meta-analysis for the indirect comparison between amoxicillin and amoxicillin-clavulanate. The revised Cochrane risk of bias tool for randomised trials was used to assess and categorise studies into low risk of bias, some concerns or high risk of bias. RESULTS: We extracted data from 44 studies including 45 400 patients. We found no evidence of a differential effect on clinical resolution when comparing amoxicillin with other antibiotics (n=15 trials; pooled OR 0.88; 95% CI 0.56 to 1.38, where >1 favours amoxicillin) or amoxicillin-clavulanate with other antibiotics (n=17; OR 0.89; 95% CI 0.76 to 1.04). Similarly, evidence of difference in clinical failure between amoxicillin and other antibiotics was unclear and unable to rule out clinically important benefits or harms (n=8; OR 0.76; 95% CI 0.55 to 1.06, where <1 favours amoxicillin). We found no evidence of a differential effect on clinical resolution between adults treated with amoxicillin and amoxicillin-clavulanate (n=28; OR 1.04; 95% CI 0.64 to 1.70, where >1 favours amoxicillin-clavulanate). Sixty-three per cent and 29% of amoxicillin and amoxicillin-clavulanate studies, respectively, had low risk of bias according to the Cochrane risk of bias tool for randomised trials. CONCLUSIONS: Current evidence is unclear as to whether amoxicillin or amoxicillin-clavulanate differs from other antibiotics, or from each other, in the treatment of community-acquired pneumonia, owing to the small number of trials and substantial heterogeneity in comparators used across study settings. PROSPERO REGISTRATION NUMBER: CRD42024568554.