Cardiopulmonary bypass (CPB) in cardiac surgery is associated with a high risk of postoperative neurological complications. Perioperative use of vasopressors is common to counteract arterial hypotension in this setting. However, use of α-agonist vasopressors has been associated with cerebral desaturations. Given that reductions in cerebral oxygen saturation (Sc⁢O2) can increase postoperative neurological dysfunction, we aimed to investigate the impact of noradrenaline (NA) and phenylephrine (PE) on Sc⁢O2 during the CPB period of a cardiac surgery in 36 patients scheduled for an elective cardiac surgery. Patients were randomized to the intra-operative use of either NA or PE. During CPB, mean arterial pressure (MAP) was elevated pharmacologically to predefined thresholds of 60 and 80 mmHg, while CPB flow was kept constant. The Sc⁢O2 values were recorded for 5 min per MAP threshold. The MAP increased adequately between thresholds of 60 and 80 mmHg (NA, 59 ± 3 vs. 81 ± 3 mmHg and PE, 61 ± 4 vs. 81 ± 3 mmHg; P ˂ 0.01). The Sc⁢O2 decreased between pressure thresholds of 60 and 80 mmHg (NA, 70 ± 11 vs. 69 ± 11 mmHg and PE, 64 ± 11 vs. 63 ± 11 mmHg; P ˂ 0.01). Reduction in Sc⁢O2 did not differ between vasopressors. The mean relative decrease in Sc⁢O2 across groups was 2.0% (95% confidence interval: 0.6 to 2.1). Elevation in MAP mediated solely by vasopressors induces significant decreases in Sc⁢O2 during cardiac surgery under CPB. However, their impact on Sc⁢O2 remains clinically non-significant according to current guidelines.