Antimicrobial resistance (AMR) poses a significant global health challenge, and antimicrobial stewardship (AMS) initiatives are acknowledged as vital measures to enhance antibiotic utilization in healthcare facilities. Nevertheless, the effective execution of AMS programs continues to be exceptionally difficult across various healthcare environments. This opinion paper consolidates findings globally to pinpoint the primary obstacles and emerging viewpoints related to the implementation of hospital-based AMS. The analysis indicates that the challenges are complex, encompassing organizational, structural, cultural, educational, and behavioural aspects. Deficiencies in leadership and governance at various institutional tiers create a lack of accountability and commitment, while insufficient human and financial resources—including a shortage of infectious disease specialists, clinical pharmacists, and microbiologists—compromise the sustainability of these programs. Deeply rooted professional hierarchies and power dynamics among healthcare disciplines hinder interprofessional collaboration and diminish the acceptance of stewardship recommendations. Knowledge deficits and a lack of AMS-specific training across all professional categories further limit implementation, as do inadequate diagnostic laboratory capabilities and restricted health information technology. A persistent gap between national policies and local implementation realities leads to guidelines that are poorly suited to institutional contexts, while mandatory strategies may result in unintended outcomes such as regulatory evasion and decreased motivation among healthcare workers. These challenges are intensified in low- and middle-income countries but remain significant even in well-resourced environments. Promising strategies encompass multidisciplinary team approaches, governmentled accountability frameworks, contextualized implementation plans, and expanded roles for healthcare professionals.