Background The acute effects of resistance training (RT) set structure alteration are well established; however, less is known about their effects on chronic training adaptations. Objective The aim of this systematic review and meta-analysis was to synthesise the available evidence on the effectiveness of traditional (TS), cluster (CS) and rest redistribution (RR) set structures in promoting chronic RT adaptations, and provide an overview of the factors which might differentially influence the magnitude of specific training adaptations between set structure types. Methods This review was performed using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines encompassing the literature search of five databases. Studies in English that compared muscular strength, endurance, and/or hypertrophy adaptations, as well as vertical jump performance, velocity and power at submaximal loads and shifts in the slopes of force-velocity profiles between TS and CS or RR set structures (i.e., alternative set structures) were included. Risk of bias assessment was performed using a modified Cochrane Collaboration's tool for assessing risk of bias in randomised trials. Random-effects meta-analyses and meta-regressions were performed where possible. Results 17 studies met the inclusion criteria, none had more than one risk of bias item assessed as high risk. Pooled results revealed that none of the set structures were more effective at inducing strength (standardised mean difference (SMD) = - 0.06) or hypertrophy (SMD = - 0.03). TS were more effective at improving muscular endurance compared to alternative set structures (SMD = - 0.38), whereas alternative set structures tended to be more effective for vertical jump performance gains (SMD = 0.13), but this effect was not statistically significant (p = 0.190). Greater velocity and power outputs at submaximal loads (SMD = 0.18) were observed when using alternative set structures compared to TS. In addition, alternative set structures promoted greater shifts of the slope of force-velocity profiles towards more velocity dominant profiles compared to TS (SMD = 0.28). Sub-group analyses controlling for each alternative set structure independently showed mixed results likely caused by the relatively small number of studies available for some outcomes. Conclusion Modifying TS to an alternative set structure (CS or RR) has a negligible impact on strength and hypertrophy. Using CS and RR can lead to greater vertical jump performance, velocity and power at submaximal loads and shifts to more velocity dominant force-velocity profiles compared to training using TS. However, TS may provide more favourable effects on muscle endurance when compared to CS and RR. These findings demonstrate that altering TS to alternative set structures may influence the magnitude of specific muscular adaptations indicating set structure manipulation is an important consideration for RT program design. Protocol registration The original protocol was prospectively registered (CRD42019138954) with the PROSPERO (International Prospective Register of Systematic Reviews).