Many Native Americans in the United States have been harmed by, or become addicted to, drinking alcohol. Among contemporary Native Americans and Alaska Natives, 11.7% of all deaths are related to alcohol. By comparison, about 5.9% of global deaths are attributable to alcohol consumption. Because of negative stereotypes and biases based on race and social class, generalizations and popular misconceptions abound around the topic of Native American alcohol misuse.

A survey of death certificates from 2006 to 2010 showed that deaths among Native Americans due to alcohol are about four times as common as in the general U.S. population. They are often due to traffic collisions and liver disease, with homicide, suicide, and falls also contributing. Deaths related to alcohol among Native Americans are more common in men and among northern Plains Indians. Alaska Natives showed the lowest incidence of alcohol-related death. Alcohol misuse amongst Native Americans has been shown to be associated with development of disease, including hearing and vision problems, kidney and bladder problems, head injuries, pneumonia, tuberculosis, dental problems, liver problems, and pancreatitis. In some tribes, the rate of fetal alcohol spectrum disorder is as high as 1.5 to 2.5 per 1,000 live births, more than seven times the national average. Among Alaska Natives, the rate of fetal alcohol spectrum disorder is 5.6 per 1,000 live births.

Native American and Native Alaskan youth are far more likely to experiment with alcohol at a younger age than non-Native youth. Low self-esteem and transgenerational trauma have been associated with substance use disorders among Native American teens in the U.S. and Canada. Alcohol education and prevention programs have focused on raising self-esteem, emphasizing traditional values, and recruiting Native youth to advocate for abstinence and healthy substitution.

Historically, those Native American tribes who manufactured alcoholic drinks used them and other mind-altering substances in ritual settings and rarely for personal enjoyment. Liquor was unknown until introduced by Europeans, therefore alcohol dependence was largely unknown when European contact was made. The use of alcohol as a trade item and the practice of intoxication for fun, or to alleviate stress, gradually undermined traditional Native American culture until by the late 18th century, alcoholism was recognized as a serious problem in many Native American communities. Native American leaders campaigned with limited success to educate Native Americans about the dangers of drinking and intoxication. Legislation prohibiting the sale of alcohol to Native Americans generally failed to prevent alcohol-related social and health problems, and discriminatory legislation was abandoned in the 1950s in favor of laws passed in Native American communities by Native Americans. Modern treatment focuses on culturally appropriate strategies that emphasize traditional activities designed to promote spiritual harmony and group solidarity.

Pre-Columbian Native Americans fermented starchy seeds and roots as well as fruits from both wild and domesticated plants. Among the most common are drinks made from fermented corn, agave, and manioc. Aboriginal use of alcohol generally took place in shared spiritual experiences that often arose out of the shamanistic tradition and was invested with expectations of improved well-being, as opposed to individual enjoyment or entertainment.

Before contact, Native Americans used mind-altering substances to communicate with the spirit world, and intoxication was "associated with a quest for enlightenment, powers of healing, and the facilitation of war-making. [They related] the new phenomenon of intoxication ... to the old concepts of dreaming, communion with the spirit world, and the acquisition of power." Aberrant behavior while intoxicated was frequently forgiven (for example, among the Catawba and the Lakota Sioux) as though the drinker had been possessed by powers beyond their control.

Pre-Columbian Mesoamericans in Mexico and Central America prepared over forty different alcoholic beverages from a variety of plants and plant extracts. Traditional Mayan beverages have included:

Traditional drinks made from fermented corn or corn flour include tejuino, pozol, chicha or chicha de jora, and pox.