Multidrug-resistant (MDR) Acinetobacter baumannii has emerged as a major global health concern due to itsremarkable ability to survive in hospital environments and develop resistance to multiple antibiotic classes. Thissystematic review synthesizes evidence from 2015 to 2025 on the efficacy, safety, and clinical outcomes of variousantibiotic regimens used in managing MDR Acinetobacter baumannii infections. A comprehensive search acrossPubMed, ScienceDirect, Scopus, Google Scholar, and the Cochrane Library identified relevant studies, whichwere screened and appraised using PRISMA 2020 guidelines. Findings reveal that traditional monotherapies suchas colistin and tigecycline exhibit moderate efficacy and significant toxicity, whereas combination therapies—particularly colistin with rifampicin or carbapenems—demonstrate higher clinical cure rates and reducedmortality. The novel siderophore cephalosporin cefiderocol achieved the best outcomes, with clinical cure ratesup to 80% and the lowest mortality (≈22.5%), attributed to its ability to overcome β-lactamase–mediated resistancemechanisms. Evidence strongly supports the use of combination and novel regimens over monotherapy to enhancetherapeutic success and minimize toxicity. Strengthening antimicrobial stewardship and continuous surveillanceare imperative to combat the growing threat of MDR Acinetobacter baumannii and preserve antibiotic efficacy.