Acinetobacter baumannii, a multidrug-resistant pathogen, poses a critical challenge in healthcare settings due to its adaptability and limited treatment options. The global rise in antimicrobial resistance (AMR) has underscored the urgent need for novel therapeutic strategies to combat infections caused by extensively drug-resistant (EDR) and pan-drug-resistant (PDR) A. baumannii. Traditional antibiotic discovery methods, such as whole-cell screening, have fallen short, consistently identifying drugs prone to resistance. This review explores the discovery of new anti-bacterial agents targeting A. baumannii, focusing on emerging therapeutic approaches, including nanoparticle-based therapies, antimicrobial peptides, and antibiotic combination therapies. Nanoparticle-based approaches, leveraging enhanced penetration and multi-mechanistic action, show promise in overcoming resistance, though challenges such as toxicity and biocompatibility persist. Additionally, combination therapies, such as polymyxins with carbapenems, have demonstrated efficacy in clinical settings. This review also highlights the limitations of current therapies, the mechanisms of bacterial resistance, and the role of alternative strategies like bacteriophage therapy. Emphasis is placed on the need for further research into overcoming cross-resistance and enhancing therapeutic efficacy against A. baumannii. The review concludes by discussing the importance of advancing research into novel agents, optimizing dosage strategies, and addressing the challenges posed by toxicity to ensure the effective treatment of A. baumannii infections in both hospital and community settings.