There has been considerable debate over the optimal number of sets per exercise to improve musculoskeletal strength during a resistance exercise program. The purpose of this study was to use hierarchical, random-effects meta-regression to compare the effects of single and multiple sets per exercise on dynamic strength. English-language studies comparing single with multiple sets per exercise, while controlling for other variables, were considered eligible for inclusion. The analysis comprised 92 effect sizes (ESs) nested within 30 treatment groups and 14 studies. Multiple sets were associated with a larger ES than a single set (difference = 0.26 +/- 0.05; confidence interval [CI]: 0.15, 0.37; p < 0.0001). In a dose-response model, 2 to 3 sets per exercise were associated with a significantly greater ES than 1 set (difference = 0.25 +/- 0.06; CI: 0.14, 0.37; p = 0.0001). There was no significant difference between 1 set per exercise and 4 to 6 sets per exercise (difference = 0.35 +/- 0.25; CI: -0.05, 0.74; p = 0.17) or between 2 to 3 sets per exercise and 4 to 6 sets per exercise (difference = 0.09 +/- 0.20; CI: -0.31, 0.50; p = 0.64). There were no interactions between set volume and training program duration, subject training status, or whether the upper or lower body was trained. Sensitivity analysis revealed no highly influential studies, and no evidence of publication bias was observed. In conclusion, 2 to 3 sets per exercise are associated with 46% greater strength gains than 1 set, in both trained and untrained subjects.