In 2024, the European Confederation of Medical Mycology, the International Society for Human and Animal Mycology, and the American Society for Microbiology jointly published the first global clinical guideline for cryptococcosis in The Lancet Infectious Diseases, which systematically established differentiated diagnostic and treatment strategies tailored to distinct host types and infection sites. This article provides an in-depth interpretation of the guideline, focusing on critical clinical aspects including diagnosis and screening of cryptococcal infection, management of central nervous system (CNS) infections, pulmonary infections, non-CNS/non-pulmonary infections, intervention strategies for complications such as immune reconstitution syndrome, and individualized treatment recommendations for special populations (pregnant women and children). The article aims to deliver standardized and actionable clinical guidance for healthcare providers, facilitating optimized comprehensive management of cryptococcosis across multi-tier healthcare institutions.