Purpose This study aimed to analyze the effect of resistance training (RT) performed until volitional failure with low, moderate, and high loads on muscle hypertrophy and muscle strength in healthy adults and to assess the possible participant-, design-, and training-related covariates that may affect the adaptations. Methods Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, MEDLINE, CINAHL, EMBASE, SPORTDiscus, and Web of Science databases were searched. Including only studies that performed sets to volitional failure, the effects of low- (>15 repetitions maximum (RM)), moderate- (9-15 RM), and high-load (<= 8 RM) RTs were examined in healthy adults. Network meta-analysis was undertaken to calculate the standardized mean difference (SMD) between RT loads in overall and subgroup analyses involving studies deemed of high quality. Associations between participant-, design-, and training-related covariates with SMD were assessed by univariate and multivariate network meta-regression analyses. Results Twenty-eight studies involving 747 healthy adults were included. Although no differences in muscle hypertrophy between RT loads were found in overall (P = 0.113-0.469) or subgroup analysis (P = 0.871-0.995), greater effects were observed in untrained participants (P = 0.033) and participants with some training background who undertook more RT sessions (P = 0.031-0.045). Muscle strength improvement was superior for both high-load and moderate-load compared with low-load RT in overall and subgroup analysis (SMD, 0.60-0.63 and 0.34-0.35, respectively; P < 0.001-0.003), with a nonsignificant but superior effect for high compared with moderate load (SMD, 0.26-0.28, P = 0.068). Conclusions Although muscle hypertrophy improvements seem to be load independent, increases in muscle strength are superior in high-load RT programs. Untrained participants exhibit greater muscle hypertrophy, whereas undertaking more RT sessions provides superior gains in those with previous training experience.