OBJECTIVE: Fatigue is a significant contributor to the burden experienced by patients with chronic disorders. The development of standardized treatments is challenging due to the lack of consensus concerning the etiology of fatigue. The aim of this systematic review is to provide an overview of non-pharmacological interventions for fatigue. The efficacy and differences in fatigue treatment across conditions will be explored. METHODS: A systematic literature search was conducted using the databases PubMed, Web of Science, PsycInfo and CINAHL. Trials were eligible when (1) adult patients (≥ 18 years old) with disorders causing fatigue were included, (2) non-pharmacological interventions performed, (3) treatment was compared to standard care, placebo or active control group, (4) fatigue was the only primary outcome assessed with a multidimensional tool, and (5) a randomized controlled trial (RCT) design was applied. RESULTS: 7592 papers were screened. 91 RCTs were eligible, with data reported in 95 papers. Specific fatigue interventions were present for a broad range of conditions. Findings demonstrated promising evidence for physical activity, CBT, online programs and multidimensional modules. Additional types of interventions were effective, but evidence was limited due to risk of bias and small sample sizes. Due to high heterogeneity concerning methodology, a meta-analysis was not possible. CONCLUSION: Several non-pharmacological treatment options for fatigue are promising. No clear evidence was found that fatigue should be treated differently depending on the underlying condition. However, further research is necessary with a focus on a transdiagnostic approach to fatigue, high study quality and long-term follow-ups.