Noncommunicable diseases (NCDs) (e.g., cardiovascular diseases, cancers, diabetes, and chronic respiratory diseases) and mental health conditions (e.g., Alzheimer’s disease and related dementias, depression, anxiety, autism spectrum disorders) are the world’s leading cause of preventable illness, disability, and death. This report examines the dangers posed by current and rising rates of noncommunicable diseases and mental health conditions (NMHs) in South America, beyond their health risks, by demonstrating their considerable negative impact on economic growth. An analytical model was developed that projects the macroeconomic effects of NMHs over the period 2020–2050 in ten South American countries: Argentina, Bolivia (Plurinational State of), Brazil, Chile, Colombia, Ecuador, Paraguay, Peru, Uruguay, and Venezuela. The results showed that the macroeconomic impact of NMHs in South America indicates significant economic shortfalls resulting from NMHs. Overall, the total GDP loss due to NMHs in South America amounts to USD 7.3 trillion (2022 international USD) over the period 2020–2050