Acinetobacter baumannii is a common multidrug-resistant pathogen causing nosocomial infections. Its resistance to antibiotics is increasing due to factors like unregulated antibiotic use. A. baumannii has high resistance rates to drugs like tigecycline and polymyxin, which are last-line treatments for extensively drug-resistant strains. Patients with severe infections have high mortality and poor prognosis, making treatment challenging. A. baumannii has developed strong resistance to carbapenem antibiotics, which were once considered effective. Understanding its resistance mechanisms is crucial for clinical treatment and new antibiotic development. This review summarizes the mechanisms of antimicrobial resistance in A. baumannii, particularly those related to tigecycline and polymyxin resistance. It serves as a reference for rational antibiotic use and new drug development. The resistance mechanisms include β-lactamase production, aminoglycoside-modifying enzymes, 16S rRNA methylase, DNA gyrase and topoisomerase gene mutations, plasmid quinolone resistance genes, changes in outer membrane pore proteins, alterations in PBPs, biofilm formation, and external discharge pump system overexpression. Tigecycline resistance in A. baumannii is influenced by efflux pump overexpression, outer membrane permeability alterations, drug target alterations, modified enzyme-mediated resistance, and DNA damage induction. Polymyxin resistance mechanisms include LPS and lipid A loss, LPS structure modification, plasmid-mediated resistance, efflux pump resistance, and outer membrane component protein mutations. These mechanisms contribute to the increasing resistance of A. baumannii to antibiotics, posing a significant challenge to clinical treatment. Understanding these mechanisms is essential for developing effective strategies to combat drug-resistant strains.Acinetobacter baumannii is a common multidrug-resistant pathogen causing nosocomial infections. Its resistance to antibiotics is increasing due to factors like unregulated antibiotic use. A. baumannii has high resistance rates to drugs like tigecycline and polymyxin, which are last-line treatments for extensively drug-resistant strains. Patients with severe infections have high mortality and poor prognosis, making treatment challenging. A. baumannii has developed strong resistance to carbapenem antibiotics, which were once considered effective. Understanding its resistance mechanisms is crucial for clinical treatment and new antibiotic development. This review summarizes the mechanisms of antimicrobial resistance in A. baumannii, particularly those related to tigecycline and polymyxin resistance. It serves as a reference for rational antibiotic use and new drug development. The resistance mechanisms include β-lactamase production, aminoglycoside-modifying enzymes, 16S rRNA methylase, DNA gyrase and topoisomerase gene mutations, plasmid quinolone resistance genes, changes in outer membrane pore proteins, alterations in PBPs, biofilm formation, and external discharge pump system overexpression. Tigecycline resistance in A. baumannii is influenced by efflux pump overexpression, outer membrane permeability alterations, drug target alterations, modified enzyme-mediated resistance, and DNA damage induction. Polymyxin resistance mechanisms include LPS and lipid A loss, LPS structure modification, plasmid-mediated resistance, efflux pump resistance, and outer membrane component protein mutations. These mechanisms contribute to the increasing resistance of A. baumannii to antibiotics, posing a significant challenge to clinical treatment. Understanding these mechanisms is essential for developing effective strategies to combat drug-resistant strains.