Abstract During the ongoing COVID-19 pandemic, face masks are among the most common and practical control measures used globally in reducing the risk of infection and disease transmission. Although several studies have investigated the efficacy of various face masks and respirators in preventing infection, the results have been inconsistent. Therefore, we performed a systematic review and network meta-analysis (NMA) of the randomized-controlled trials (RCTs) to assess the actual efficacy of face masks in preventing respiratory infections. We searched nine electronic databases up to July 2020 to find potential articles. We accepted trials reporting the protective efficacy of face masks against respiratory infections, of which the primary endpoint was the presence of respiratory infections. We used the ROB-2 Cochrane tool to grade the trial quality. We initially registered the protocol for this study in PROSPERO (CRD42020178516). Sixteen RCTs involving 17 048 individuals were included for NMA. Overall, evidence was weak, lacking statistical power due to the small number of participants, and there was substantial inconsistency in our findings. In comparison to those without face masks, participants with fit-tested N95 respirators were likely to have lesser infection risk (RR 0.67, 95% CI 0.38–1.19, P-score 0.80), followed by those with non-fit-tested N95 and non-fit-tested FFP2 respirators that shared the similar risk, (RR 0.73, 95% CI 0.12–4.36, P-score 0.63) and (RR 0.80, 95% CI 0.38–1.71, P-score 0.63), respectively. Next, participants who donned face masks with and without hand hygiene practices showed modest risk improvement alike (RR 0.89, 95% CI 0.67–1.17, P-score 0.55) and (RR 0.92, 95% CI 0.70–1.22, P-score 0.51). Otherwise, participants donning double-layered cloth masks were prone to infection (RR 4.80, 95% CI 1.42–16.27, P-score 0.01). Eleven out of 16 RCTs that underwent a pairwise meta-analysis revealed a substantially lower infection risk in those donning medical face masks (MFMs) than those without face masks (RR 0.83 95% CI 0.71–0.96). Given the body of evidence through a systematic review and meta-analyses, our findings supported the protective benefits of MFMs in reducing respiratory transmissions, and the universal mask-wearing should be applied—especially during the COVID-19 pandemic. More clinical data is required to conclude the efficiency of cloth masks; in the short term, users should not use cloth face masks in the outbreak hot spots and places where social distancing is impossible.