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Objective: Down syndrome or trisomy 21 is one of the most common human chromosomal disorders that affect cognitive functions, communication and behavioral skills. At the macro level, various factors can contribute to the Down syndrome prevalence and mortality. This study aimed to investigate the association of health system functions with Down syndrome prevalence and mortality worldwide. Materials & Methods: The study was a cross-sectional study conducted based on the secondary analysis of existing data in 2019. Data from 202 countries in six different regions (African Region [AFRO], Eastern Mediterranean Region [EMRO], European Region [EURO], South-East Asia Region [SEARO], Western Pacific Region [WPRO], and Pan American Health Organization [PAHO]) were included in the study. Data were extracted from the World Health Organization (WHO), the World Bank and the Institute for Health Metrics and Evaluation databases. The adjusted linear regression analysis was used to examine the association between health system-related factors with prevalence of, and death due to Down syndrome as the outcome variables. In the present study, two functions of health financing (domestic general government health expenditure [GGHE-D] per capita in PPP [purchasing power parity] int$, domestic private health expenditure [PHE-D] per capita in PPP int$, external health expenditure [EXT] per capita in PPP int$) and health system resources (nurse and midwifery personnel, generalist medical practitioners [GMP], specialist medical practitioners [SMP], pharmacists, dentists, physiotherapists) were included in the study as independent variables. We used the Stata software version 14 to analyze Results: Africa and low-income countries had the highest deaths due to Down syndrome. On the other side, Europe and high-income countries had the highest prevalence of Down syndrome worldwide. According to the available data, Iran had a lower prevalence (29.31 vs 38.44 per 100,000 population) and higher deaths (0.34 vs 0.32 per 100,000 population) compared to high- income countries. The 20-year trend of prevalence of, and deaths due to Down syndrome in Iran has always been lower and higher than high-income countries, respectively. Linear regression analysis showed that GGHE-D per capita (β=0.385, P