Background <p>Baclofen is a γ-aminobutyric acid type B receptor agonist primarily used for spasticity. It is increasingly prescribed orally at high off-label doses for conditions such as alcohol use disorder, raising concerns regarding severe toxicity and withdrawal syndromes. This systematic review comprehensively characterizes the clinical presentations, management strategies, and outcomes associated with oral baclofen toxicity and withdrawal.</p> Methods <p>MEDLINE, Embase, and CENTRAL databases were searched from inception through October 2024. Eligible studies included clinical trials, observational studies, case series, and case reports describing oral baclofen toxicity or withdrawal in humans. Excluded were studies on intrathecal baclofen, non-human or preclinical data, gray literature, and reports lacking sufficient clinical data. Three reviewers independently performed study screening, data extraction, and quality assessments. The Joanna Briggs Institute Critical Appraisal Checklists for case reports, case series, and observational studies were used to evaluate methodological quality and risk of bias across included studies. Discrepancies were resolved by consensus among reviewers, with senior author verification when needed. Outcome measures included clinical presentation, management strategies, need for intensive care or mechanical ventilation, length of hospital stay, recovery status, and mortality. Because of study heterogeneity, data were synthesized narratively without a formal certainty assessment.</p> Results <p>Sixty-six case reports (44 toxicity cases from 38 case reports, 34 withdrawal cases from 28 case reports) and 18 retrospective studies (<i>n</i> = 1540) were included (total <i>n</i> = 1618 individuals). Baclofen toxicity commonly presented with central nervous system depression (68%), seizures (36%), and respiratory depression (21%), particularly at doses ≥ 300 mg. Management predominantly involved supportive measures, including mechanical ventilation in approximately 54.5% of cases. Full clinical recovery occurred in 97.7% of cases. In retrospective cohorts, mortality was generally low (~ 0–4%), with most patients recovering following supportive management. Baclofen withdrawal commonly manifested with severe psychiatric disturbances (up to 20.6%), delirium, agitation, and autonomic instability, typically emerging within 1–4 days after abrupt discontinuation. Rapid baclofen reinitiation consistently resolved withdrawal symptoms.</p> Conclusions <p>Baclofen toxicity and withdrawal can become severe or life threatening, underscoring the need for prompt recognition and careful medical management. Clinicians should exercise caution when prescribing baclofen, particularly at higher doses (≥ 300 mg/day). Prospective studies and standardized clinical guidelines are needed to enhance patient safety and optimize outcomes.</p> <p>PROSPERO number CRD420251155708.</p>