Antimicrobial resistance (AMR) has emerged as one of the most pressing global public health crises of the 21st century, threatening to reverse decades of progress in infectious disease control. This study aims to systematically analyze the multifaceted challenges of AMR from a global governance perspective, evaluate the progress made by international, regional, and national governance initiatives, and propose evidence-based future directions to strengthen AMR governance. A mixed-methods approach was adopted, integrating a systematic review of 180 peer-reviewed studies and policy documents (2015–2024), case studies of 15 countries across different income levels and regions, and semi-structured interviews with 120 stakeholders (policymakers, healthcare providers, researchers, and industry representatives). The findings reveal that AMR governance faces four core challenges: (1) Fragmented governance structures with inadequate coordination among international organizations, governments, and non-state actors; (2) Unequal access to quality antimicrobials and diagnostic tools between high-income countries (HICs) and low- and middle-income countries (LMICs); (3) Insufficient investment in AMR surveillance, research and development (R&D) of new antimicrobials, and infection prevention and control (IPC) measures; (4) Lack of effective mechanisms to regulate antimicrobial use in human, animal, and environmental sectors (the “One Health” gap). Despite these challenges, significant progress has been made, including the adoption of the WHO Global Action Plan on AMR, the establishment of regional AMR surveillance networks, and the implementation of national AMR action plans in over 170 countries. However, implementation gaps remain, particularly in LMICs, due to limited resources, weak health systems, and inadequate technical capacity. Case study analysis shows that countries with strong intersectoral collaboration, robust surveillance systems, and targeted investments in IPC have achieved better AMR control outcomes. The study proposes four key future directions for strengthening AMR governance: (1) Establish a centralized global AMR governance body to enhance coordination; (2) Promote equitable access to antimicrobials and diagnostics through innovative financing mechanisms; (3) Increase global investment in AMR R&D and surveillance, with a focus on LMIC needs; (4) Accelerate the adoption and implementation of One Health approaches at all levels. This study emphasizes that addressing AMR requires a coordinated, multi-sectoral, and equity-centered global governance response, and provides actionable insights for policymakers, international organizations, and other stakeholders to advance AMR control efforts.