Objectives. To examine food insecurity and cardiovascular disease-related health outcomes among American Indians (AIs) in rural Oklahoma. Methods. We surveyed a cross-sectional sample of 513 AI adults to assess food insecurity domains (i.e., food quality and quantity) and obesity, diabetes, and hypertension. Results. Among AIs surveyed, 56% reported inadequate food quantity and 62% reported inadequate food quality.The unadjusted prevalence of diabetes (28.4% vs 18.4%), obesity (60.0% vs 48.3%), and hypertension (54.1% vs 41.6%) was higher among participants with inadequate food quantity than among those with adequate food quantity. These associations did not reach statistical significance after adjustment for age, gender, study site, education, and income. The unadjusted prevalence of obesity (60.7% vs 45.8%), diabetes (27.3% vs 18.8%), and hypertension (52.5% vs 42.5%) was higher among those with inadequate food quality than among those with adequate food quality, even after adjustment for age, gender, study site, education, and income. Conclusions.Tribal, federal, and state policymakers, as well as businesses and nonprofit organizations, must collaboratively take aggressive action to address food insecurity and its underlying causes, including improving tribal food environments, reducing barriers to healthy foods, and increasing living wages.