Objectives To examine the use of face mask intervention in mitigating the risk of spreading respiratory infections and whether the effect of face mask intervention differs in different exposure settings and age groups. Design Systematic review and meta-analysis. We evaluated the risk of bias using the Cochrane Risk of Bias 2 tool (ROB2). Data sources We searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched for randomized controlled trials investigating the effect of face masks on respiratory infections published between 1981 and February 9, 2022. We followed the PRISMA 2020 guidelines. Eligibility criteria for selecting studies We included randomized controlled trials investigating the use of face mask intervention in mitigating the risk of spreading respiratory infections across different exposure settings. Results We identified 2,400 articles for screening. 18 articles passed the inclusion criteria for both evidence synthesis and meta-analysis. There were N = 189,145 individuals in the face mask intervention arm and N = 173,536 in the control arm, and the follow-up times ranged from 4 days to 19 months. Our results showed between-study heterogeneity (p < 0.0001). While there was no statistically significant association over all studies when the covariate unadjusted intervention effect estimates were used (RR = 0.977 [0.858–1.113], p = 0.728), our subgroup analyses revealed that a face mask intervention reduced respiratory infections in the adult subgroup (RR = 0.8795 [0.7861–0.9839], p = 0.0249) and in a community setting (RR = 0.890 [0.812–0.975], p = 0.0125). Furthermore, our leave-one-out analysis found that one study biased the results towards a null effect. Consequently, when using covariate adjusted odds ratio estimates to have a more precise effect estimates of the intervention effect to account for differences at the baseline, the results showed that a face mask intervention did reduce respiratory infections when the biasing study was excluded from the analysis (OR = 0.8892 [0.8061–0.9810], p = 0.0192). Conclusion Our findings support the use of face masks particularly in a community setting and for adults. We also observed substantial between-study heterogeneity and varying adherence to protocol. Notably, many studies were subject to contamination bias thus affecting the efficacy of the intervention, that is when also some controls used masks or when the intervention group did not comply with mask use leading to a downward biased effect of treatment receipt and efficacy. Trial registration PROSPERO registration number CRD42020205523.