Aging is associated with elevated blood pressure, vascular oxidative stress and emotional behavioral abnormalities, such as anxiety and depression. Angiotensin II (Ang II) is reportedly involved in both vascular and emotional behavioral abnormalities. The actions of Ang II are mediated by the Ang II type 1 receptor whose activity is modulated by regulator of G‐protein signaling 5 (RGS5) protein. We have previously reported that RGS5 deficiency exacerbates Ang II‐induced elevations in blood pressure, and emotional behaviors in the absence and presence of elevated Ang II levels in adult (~26 week old) male mice. In this study we assessed the role of RGS5 on blood pressure, vascular and emotional behavioral outcomes in aged male mice in the absence and presence of elevated Ang II levels (1 mg/kg/d for 21 days). Specifically, we used aged (16–20 month old) male mice lacking RGS5 and their wild type counterparts to assess effects of saline or Ang II on systolic blood pressure (SBP), vascular function and oxidative stress, locomotor activity, and anxiety‐ and depression‐like behavior. RGS5 deficiency increased SBP under normal conditions, and increased cerebral vascular superoxide levels in the absence and presence of elevated Ang II levels, suggesting that RGS5 deficiency leads to elevated blood pressure and cerebral vascular oxidative stress in aged mice. RGS5 deficiency did not impair relaxation responses to acetylcholine, or contraction to the nitric oxide synthase inhibitor l‐NAME in aorta, suggesting that RGS5 deficiency had no effect on endothelial function in aorta. Interestingly, elevated Ang II levels increased spontaneous locomotor activity in wild‐type mice, but not in mice lacking RGS5. These data suggest that RGS5 deficiency attenuated responsiveness to Ang II‐induced increases in spontaneous locomotor activity. RGS5 deficiency and Ang II treatment had no effect on anxiety‐ and depression‐like behavior. In summary, these data suggest that RGS5 protects against elevated blood pressure, and has protective effects in the cerebral circulation in the absence and presence of elevated Ang II levels in aged male mice. Clinically, these data suggest that inhibitors of the renin angiotensin system may reduce the risk of cerebrovascular disease in aged males lacking RGS5.Support or Funding InformationThis work was supported by funds from the College of Pharmacy, Ohio Northern University.