Background Quality of the peer‐review process has been tested only in small studies. We describe and summarize the randomized trials that investigated interventions aimed at improving peer‐review process of biomedical manuscripts. Methods and Results All randomized trials comparing different peer‐review interventions at author‐, reviewer‐, and/or editor‐level were included. Differences between traditional and intervention‐modified peer‐review processes were pooled as standardized mean difference (SMD) in quality based on the definitions used in the individual studies. Main outcomes assessed were quality and duration of the peer‐review process. Five‐hundred and seventy‐five studies were retrieved, eventually yielding 24 randomized trials. Eight studies evaluated the effect of interventions at author‐level, 16 at reviewer‐level, and 3 at editor‐level. Three studies investigated interventions at multiple levels. The effects of the interventions were reported as mean change in review quality, duration of the peer‐review process, acceptance/rejection rate, manuscript quality, and number of errors detected in 13, 11, 5, 4, and 3 studies, respectively. At network meta‐analysis, reviewer‐level interventions were associated with a significant improvement in review quality (SMD, 0.20 [0.06 to 0.33]), at the cost of increased duration of the review process (SMD, 0.15 [0.01 to 0.29]), except for reviewer blinding. Author‐ and editor‐level interventions did not significantly impact peer‐review quality and duration (respectively, SMD, 0.17 [−0.16 to 0.51] and SMD, 0.19 [−0.40 to 0.79] for quality, and SMD, 0.17 [−0.16 to 0.51] and SMD, 0.19 [−0.40 to 0.79] for duration). Conclusions Modifications of the traditional peer‐review process at reviewer‐level are associated with improved quality, at the price of longer duration. Further studies are needed. Registration URL: https://www.crd.york.ac.uk/prospero ; Unique identifier: CRD42020187910.