Background Although many studies on the association between dyslipidemia and cardiovascular disease (CVD) exist in older adults, data on the association among adolescents and young adults living with disproportionate burden of cardiometabolic disorders are scarce. Methods and Results The SHFS (Strong Heart Family Study) is a multicenter, family‐based, prospective cohort study of CVD in an American Indian populations, including 12 communities in central Arizona, southwestern Oklahoma, and the Dakotas. We evaluated SHFS participants, who were 15 to 39 years old at the baseline examination in 2001 to 2003 (n=1440). Lipids were measured after a 12‐hour fast. We used carotid ultrasounds to detect plaque at baseline and follow‐up in 2006 to 2009 (median follow‐up=5.5 years). We identified incident CVD events through 2020 with a median follow‐up of 18.5 years. We used shared frailty proportional hazards models to assess the association between dyslipidemia and subclinical or clinical CVD, while controlling for covariates. Baseline dyslipidemia prevalence was 55.2%, 73.6%, and 78.0% for participants 15 to 19, 20 to 29, and 30 to 39 years old, respectively. Approximately 2.8% had low‐density lipoprotein cholesterol ≥160 mg/dL, which is higher than the recommended threshold for lifestyle or medical interventions in young adults of 20 to 39 years old. During follow‐up, 9.9% had incident plaque (109/1104 plaque‐free participants with baseline and follow‐up ultrasounds), 11.0% had plaque progression (128/1165 with both baseline and follow‐up ultrasounds), and 9% had incident CVD (127/1416 CVD‐free participants at baseline). Plaque incidence and progression were higher in participants with total cholesterol ≥200 mg/dL, low‐density lipoprotein cholesterol ≥160 mg/dL, or non–high‐density lipoprotein cholesterol ≥130 mg/dL, while controlling for covariates. CVD risk was independently associated with low‐density lipoprotein cholesterol ≥160 mg/dL. Conclusions Dyslipidemia is a modifiable risk factor that is associated with both subclinical and clinical CVD, even among the younger American Indian population who have unexpectedly high rates of significant CVD events. Therefore, this population is likely to benefit from a variety of evidence‐based interventions including screening, educational, lifestyle, and guideline‐directed medical therapy at an early age.