Cushing’s Syndrome (CS) is a multifaceted endocrine disorder resulting from chronic exposure to elevated cortisol levels. This guide addresses key gaps in current clinical practice by integrating evidence-based diagnostic protocols with a patient-centered management strategy. It distinguishes between Cushing’s syndrome and Cushing’s disease, highlighting their unique diagnostic and therapeutic considerations. Special attention is given to pediatric presentations, rare etiologies, and atypical manifestations, ensuring a comprehensive clinical perspective. Structured algorithms streamline screening, second-line investigations, and treatment pathways, covering both pharmacological and surgical interventions. Guidance is also provided on managing associated comorbidities, long-term monitoring, and coordinating multidisciplinary care. Through practical insights and clinical examples, this guide empowers clinicians to manage hypercortisolism with clarity, accuracy, and compassion.