Abstract... Background: Rare disease (RD) affects a small proportion of the population but collectively impose a significant healthcare burden. With over 10,000 rare conditions—80% of which are genetic—comprehensive data collection is essential. In Libya, a lack of centralized data and diagnostic infrastructure has limited understanding of disease prevalence and outcomes. The aim of this study was to establish the first national rare disease registry in Libya and provide an epidemiological overview of rare diseases to support healthcare planning and policy development. Methodology: This was a retrospective observational registry study conducted from March to November 2024. Data were collected from 625 patients across multiple healthcare centers in Libya using hospital records, clinical interviews, and genetic test results. Results: Of the 625 patients, 62.9% were male and 37.1% female, with the majority aged 5–14 years. The most prevalent disease categories were rare hematological (31.5%), neuromuscular and neurological (23.0%), and inborn errors of metabolism (20.3%). Sickle cell anemia (13.8%), Duchenne muscular dystrophy (8.6%), and cystic fibrosis (8.5%) were among the most frequently diagnosed conditions. Statistically significant variations were observed across age groups, regions, and healthcare centers (p < 0.001). Conclusion: This first national rare disease registry in Libya highlights substantial regional and age-related disparities in disease distribution. It underscores the urgent need for improved diagnostic capabilities, targeted awareness, and decentralized specialized care.