Antimicrobial resistance (AMR) is a growing global health crisis, particularly among ESKAPE pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. Among them, A. baumannii and S. aureus are major contributors to nosocomial infections, with high prevalence in intensive care units and immunocompromised patients. Their ability to resist multiple antibiotic classes complicates treatment strategies, leading to increased morbidity and mortality. Key resistance mechanisms, including biofilm formation, efflux pump activity, and horizontal gene transfer, enhance their survival and persistence. Furthermore, interactions during polymicrobial infections intensify disease severity through synergistic effects that promote both virulence and resistance. The epidemiological burden of these pathogens highlights the urgent need for novel antimicrobial strategies and targeted interventions. This review explores their virulence factors, resistance mechanisms, pathogenic interactions, and clinical implications, emphasizing the necessity of innovative therapeutic approaches to combat their growing threat.