The purpose of this systematic review is to examine mental, sociocultural, behavioral, and physical risk and protective factors related to cardiovascular disease (CVD) and related outcomes among U.S. Indigenous peoples. A total of 51 articles met the inclusion criteria of research focusing factors for CVD among U.S. Indigenous peoples (Mental n = 15; Sociocultural, n = 17; Behavioral/Physical, n = 19). This review reveals clear risks for CVD, which tended to be elevated for females. Mental health problems (depression, anxiety, PTSD/trauma, alcohol, and other drug (AOD) abuse) were clearly associated with CVD, along with enculturation, social support, and the social environment – including discrimination and trauma. Poor diet and obesity, diabetes, hypertension, cholesterol were behavioral or physical factors. Overall, identified research was limited and in beginning stages, lacking more information on etiology of the interconnections across sex and the mental, sociocultural, and behavioral determinants of CVD.