Background This is the protocol for a systematic review (and meta-analysis) of an intervention. The primary objective of this systematic review will be to assess the benefits and harms of pharmacological therapies (pharmacotherapies) for the management of fatigue in adults with CLD of any etiology. The effects of pharmacological therapies on fatigue in CLD will be compared against those of placebo, no intervention, or non-pharmacological interventions. Specifically, this review will examine whether pharmacological therapies improve CLD-associated fatigue, and if they do, what key elements are associated with their effectiveness. The results of this systematic review will assist clinicians, policy-makers, researchers, and people with CLD in decision-making on how best to manage fatigue and its associated symptoms. Methods MEDLINE, SCOPUS, EMBASE, EU Clinical Trials Register, WHO International Clinical Trials Registry Platform, CENTRAL (The Cochrane Library), ClinicalTrials.gov, reference lists of articles and conference proceedings will be searched for relevant studies. No language or date restrictions will be applied. Eligible studies will include adults with CLD of any etiology. Included studies will be randomized controlled trials. From included studies, data on participant characteristics, study design, setting, research ethics compliance, and intervention outcomes will be extracted. Risk of bias in included studies will be assessed using the Cochrane Risk of Bias Tool. A random-effects meta-analysis will be conducted. If substantial or considerable levels of heterogeneity are detected, analysis will be limited to a narrative synthesis. Discussion This systematic review will examine the effectiveness of pharmacological therapies on fatigue reduction in people with CLD. Such therapies may be more effective than non-pharmacological interventions in treating fatigue symptoms in CLD. Evidence derived from the findings of this study will guide future practice, policy, and research. Systematic review registration PROSPERO, CRD42017076957 Electronic supplementary material The online version of this article (10.1186/s13643-018-0688-7) contains supplementary material, which is available to authorized users.