Acinetobacter baumannii is a common multidrug-resistant pathogen that causes nosocomial infections. The increasing prevalence of multidrug-resistant A. baumannii infections is attributed to factors such as unregulated antibiotic use. A. baumannii has a high resistance rate, particularly to tigecycline and polymyxin, which are drugs of last resort for extensively drug-resistant infections. Patients with severe infections of extensively drug-resistant A. baumannii have a high mortality rate and poor prognosis, making treatment challenging. A. baumannii has rapidly acquired strong resistance to carbapenem antibiotics through the production of carbapenemases and other mechanisms. Understanding the resistance mechanisms of A. baumannii is crucial for effective clinical management and new antibiotic development. The review summarizes the mechanisms underlying common antimicrobial resistance in A. baumannii, focusing on tigecycline and polymyxin resistance. A. baumannii produces various antimicrobial-inactivating enzymes, such as β-lactamases, and overexpresses efflux pumps, altering antibiotic target locations and outer membrane protein permeability. β-Lactamases, including class A, B, C, and D enzymes, are the primary defense mechanism against β-lactam antibiotics. Aminoglycoside-modifying enzymes and 16S rRNA methylase are involved in aminoglycoside resistance. DNA gyrase and topoisomerase gene mutations, as well as plasmid quinolone resistance genes, contribute to quinolone resistance. Changes in outer membrane pore proteins and alterations in PBPs also enhance drug resistance. Biofilm formation and external discharge pump system overexpression further exacerbate resistance. 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-induced reactions. Polymyxin resistance mechanisms include LPS and lipid A loss, LPS structure modifications, plasmid-mediated polymyxin resistance, efflux pump resistance, and outer membrane component protein mutations. LPS loss and structure modifications, particularly PEtN addition, are key factors in polymyxin resistance. Plasmid-mediated resistance, such as the mcr gene, also plays a role. Understanding these resistance mechanisms is essential for developing effective clinical strategies and new antibiotics to combat the growing threat of multidrug-resistant A. baumannii infections.Acinetobacter baumannii is a common multidrug-resistant pathogen that causes nosocomial infections. The increasing prevalence of multidrug-resistant A. baumannii infections is attributed to factors such as unregulated antibiotic use. A. baumannii has a high resistance rate, particularly to tigecycline and polymyxin, which are drugs of last resort for extensively drug-resistant infections. Patients with severe infections of extensively drug-resistant A. baumannii have a high mortality rate and poor prognosis, making treatment challenging. A. baumannii has rapidly acquired strong resistance to carbapenem antibiotics through the production of carbapenemases and other mechanisms. Understanding the resistance mechanisms of A. baumannii is crucial for effective clinical management and new antibiotic development. The review summarizes the mechanisms underlying common antimicrobial resistance in A. baumannii, focusing on tigecycline and polymyxin resistance. A. baumannii produces various antimicrobial-inactivating enzymes, such as β-lactamases, and overexpresses efflux pumps, altering antibiotic target locations and outer membrane protein permeability. β-Lactamases, including class A, B, C, and D enzymes, are the primary defense mechanism against β-lactam antibiotics. Aminoglycoside-modifying enzymes and 16S rRNA methylase are involved in aminoglycoside resistance. DNA gyrase and topoisomerase gene mutations, as well as plasmid quinolone resistance genes, contribute to quinolone resistance. Changes in outer membrane pore proteins and alterations in PBPs also enhance drug resistance. Biofilm formation and external discharge pump system overexpression further exacerbate resistance. 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-induced reactions. Polymyxin resistance mechanisms include LPS and lipid A loss, LPS structure modifications, plasmid-mediated polymyxin resistance, efflux pump resistance, and outer membrane component protein mutations. LPS loss and structure modifications, particularly PEtN addition, are key factors in polymyxin resistance. Plasmid-mediated resistance, such as the mcr gene, also plays a role. Understanding these resistance mechanisms is essential for developing effective clinical strategies and new antibiotics to combat the growing threat of multidrug-resistant A. baumannii infections.