Background Proper design of resistance training (RT) variables is a key factor to reach the maximum potential of neuromuscular adaptations. Among those variables, the use of RT performed to failure (RTF) may lead to a diferent magnitude of acute fatigue compared with RT not performed to failure (RTNF). The fatigue response could interfere with acute adaptive changes, in turn regulating long-term adaptations. Considering that the level of fatigue afects long-term adaptations, it is important to determine how fatigue is afected by RTF versus RTNF. Objective The aim of this systematic review and meta-analysis was to compare the efects of RTF versus RTNF on acute fatigue. Methods The search was conducted in January 2021 in seven databases. Only studies with a crossover design that investigated the acute biomechanical properties (vertical jump height, velocity of movement, power output, or isometric strength), metabolic response (lactate or ammonia concentration), muscle damage (creatine kinase activity), and rating of perceived exertion (RPE) were selected. The data (mean ± standard deviation and sample size) were extracted from the included studies and were either converted into the standardized mean diference (SMD) or maintained in the raw mean diference (RMD) when the studies reported the results in the same scale. Random-efects meta-analyses were performed. Results Twenty studies were included in the systematic review and 12 were included in the meta-analysis. The main metaanalyses indicated greater decrease of biomechanical properties for RTF compared with RTNF (SMD − 0.96, 95% confdence interval [CI] − 1.43 to − 0.49, p < 0.001). Furthermore, there was a larger increase in metabolic response (RMD 4.48 mmol·L−1, 95% CI 3.19–5.78, p < 0.001), muscle damage (SMD 0.76, 95% CI 0.31–1.21, p = 0.001), and RPE (SMD 1.93, 95% CI 0.87–3.00, p < 0.001) for RTF compared with RTNF. Further exploratory subgroup analyses showed that training status (p=0.92), timepoint (p=0.89), load (p=0.10), and volume (p=0.12) did not afect biomechanical properties; however, greater loss in the movement velocity test occurred on upper limbs compared with lower limbs (p<0.001). Blood ammonia concentration was greater after RTF than RTNF (RMD 44.66 μmol·L−1, 95% CI 32.27–57.05, p < 0.001), as was 48 h post-exercise blood creatine kinase activity (SMD 0.86, 95% CI 0.33–1.42, p = 0.002). Furthermore, although there was considerable heterogeneity in the overall analysis (I2=83.72%; p<0.01), a signifcant diference in RPE after RTF compared with RTNF was only found for studies that did not equalize training volumes.