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Background NAFLD clinical trials have shown suboptimal results, particularly for liver fibrosis, despite the robust preclinical drug development. We aimed to assess the histological response after the experimental treatment versus placebo by carrying out a meta-analysis of NAFLD clinical trials. Methods After a systematic review of NAFLD clinical trials to May 2021, applying strict selection criteria, the following primary outcomes were observed: (a) NASH resolution, with no worsening of fibrosis when available; (b) fibrosis improvement  ≥ 1 stage, with no worsening of NAS when available; (c) worsening of NAS; (d) worsening of liver fibrosis  ≥ 1 stage, including the progression to cirrhosis on histopathology. Other histological, clinical, and biochemical outcomes were considered secondary endpoints. Heterogeneity was explored by subgroup and sensitivity analyses, and univariable meta-regression. Results Twenty-seven randomized clinical trials were included. The pooled efficacy for NASH resolution receiving experimental therapy was 19% (95%CI 15–23; I2 96.2%) compared with placebo 10% (95%CI 7–12; I2 85.8%) (OR 1.66 (95%CI 1.24–2.21); I2 57.8%), while it was 26% (95%CI 22–29); I2 90%)) versus 18% (95%CI 15–21; I2 59%)) for fibrosis improvement (OR 1.34 (95%CI 1.13–1.58); I2 25.4%). For these outcomes, the therapy showed higher efficacy in trials longer than 48 weeks, with  < 60% of diabetic population, and when it targeted FXR, PPAR, and antidiabetic mechanisms, and with a NAS  < 5 for NASH resolution. Also, NASH (OR 0.57 (95%CI 0.39–0.84); I2 67%) and fibrosis worsening (OR 0.65 (95%CI 0.46–0.92); I2 61.9%) were prevented with the therapy. Conclusion This meta-analysis provides information about the efficacy of the therapy versus placebo by comparing different and combined trial outcomes such as NASH resolution, fibrosis improvement, and NAS and fibrosis worsening. Changes in the experimental design and selection criteria of the clinical trials might be suitable to increase the efficacy.