Background <p>The aim of this study was to systematically review clinical trials evaluating the flupirtine to identify any biochemical or clinical indicators that could signal serious hepatotoxicity.</p> Methods <p>This systematic review included randomized controlled trials (RCTs) evaluating flupirtine-containing medicines for any clinical condition. Trials involving any population, comparator, or outcome were considered eligible for inclusion. A comprehensive search was conducted in Embase, MEDLINE, and CENTRAL from their inception until August 14, 2023. The risk of bias (RoB) in the included trials was assessed using Cochrane’s 2011 RoB tool. Due to the heterogeneity of the included trials, a meta-analysis could not be performed.</p> Results <p>A total of 35 trials published between 1983 and 2022 were included in this systematic review, with 1408 participants receiving flupirtine. Only five trials reported any data related to liver function tests. Among these, four trials documented transient, asymptomatic liver abnormalities that returned to normal after the trial period, while one trial was prematurely terminated. One trial reported normal liver test results in all participants. Of the three trials published after 2018, only one acknowledged the withdrawal of flupirtine from the European market. The majority of risk of bias (RoB) domains were classified as having an unclear risk of bias.</p> Conclusion <p>Published RCTs did not report any evidence of serious hepatotoxicity associated with flupirtine based on the available biochemical or clinical data. However, liver function test results were reported in only 5 out of 35 included trials. Published RCTs are not reliable information about flupirtine-related hepatotoxicity.</p> <p><b>Registration</b>: Protocol was published in PROSPERO (CRD42018085123).</p>