Objectives: To systematically review literature on efficacy of amantadine on behavior (irritability/aggression/agitation, emotional lability, apathy, impairment of executive functioning), participation, quality-of-life (QoL), and safety, in patients with acquired brain injury (ABI). Amantadine is widely used clinically, so comprehensive information on efficacy, participation, QoL and safety is relevant. Methods: We used PRISMA Guidelines. We searched PubMed/EMBASE/CINAHL (last search 28–8-2018) Two independent reviewers performed selection and data-extraction. Quality of studies was assessed, using CONSORT and Quality Assessment Tool for Quantitative Studies (QATFQS). Results: Eleven out of 500 studies were included. Of five RCTs, two reported significant effects on irritability/aggression, and one no effect. One RCT on cognition no effect. One prospective cohort study showed a significant effect on executive functioning. One retrospective study was inconclusive. One single-case experimental design (SCED) study reported significant effect on apathy and three case-reports indicated effects on behavior. QoL and societal participation were not measured. No safety issues emerged. Conclusion: Amantadine may be efficacious on irritability and aggression after ABI. Amantadine is a safe drug in the presence of adequate creatinine clearance. Future studies should use designs, suitable for the heterogeneous ABI population, like randomized SCEDs, and should include the effect on societal participation and QoL.