Background: Medical device-associated healthcare infections [MDHAIs] represent a critical threat to patient safety worldwide, constituting approximately 30% of nosocomial infections and imposing substantial morbidity, mortality, and financial burdens on healthcare systems. Objectives: This comprehensive review synthesizes current evidence on the epidemiology, microbiology, pathogenesis, prevention, and quality-of-life implications of MDHAIs, with emphasis on sterilization protocols, reprocessing standards, and emerging antimicrobial technologies. Methods: A systematic literature review was conducted examining device-associated infections in intensive care settings, including central line-associated bloodstream infections [CLABSI], catheter-associated urinary tract infections [CAUTI], and ventilator-associated pneumonia [VAP]. Key Findings: The epidemiology of MDHAIs continues to evolve, with multidrug-resistant [MDR] and extensively drug-resistant [XDR] pathogens demonstrating enhanced biofilm formation capacity [up to 1000-fold increased resistance to antimicrobial agents compared to planktonic cells]. Current surveillance data reveals CAUTI incidence of 1.67 per 1000 catheter-days, CLABSI at 0.59 per 1000 central line-days, and VAP at 4.63 per 1000 ventilator-days. Evidence-based prevention bundles have achieved CLABSI reductions of 60–90% and VAP reductions exceeding 40% in institutional settings. Device-associated infections profoundly impact quality of life through extended hospitalization, prolonged recovery, and significant psychological morbidity including anxiety, depression, and post-intensive care syndrome. Conclusions: Effective prevention of MDHAIs requires multifaceted approaches encompassing appropriate device classification, adherence to ISO 17664:2021 reprocessing standards, rigorous quality assurance monitoring, comprehensive staff training, implementation of bundle prevention strategies, and integration of clinical engineering expertise. Novel antimicrobial technologies [bacteriophages, endolysins, antimicrobial peptides] and anti-adhesion surface coatings offer promise for future device sterilization. Sustainability imperatives and evidence supporting reusable device efficacy warrant reconsideration of single-use device reliance, coupled with investment in institutional reprocessing infrastructure and patient-centered education.