This study investigated trans-cerebral internal jugular venous-arterial bicarbonate ([HCO₃⁻]) and carbon dioxide tension (PCO₂) exchange utilizing two separate interventions to induce acidosis: 1) acute respiratory acidosis via elevations in arterial PCO₂ (PaCO₂) (n = 39); and 2) metabolic acidosis via incremental cycling exercise to exhaustion (n = 24). During respiratory acidosis, arterial [HCO₃⁻] increased by 0.15 ± 0.05 mmol ⋅ l⁻¹ per mmHg elevation in PaCO₂ across a wide physiological range (35 to 60 mmHg PaCO₂; P < 0.001). The narrowing of the venous-arterial [HCO₃⁻] and PCO₂ differences with respiratory acidosis were both related to the hypercapnia-induced elevations in cerebral blood flow (CBF) (both P < 0.001; subset n = 27); thus, trans-cerebral [HCO₃⁻] exchange (CBF × venous-arterial [HCO₃⁻] difference) was reduced indicating a shift from net release toward net uptake of [HCO₃⁻] (P = 0.004). Arterial [HCO₃⁻] was reduced by −0.48 ± 0.15 mmol ⋅ l⁻¹ per nmol ⋅ l⁻¹ increase in arterial [H⁺] with exercise-induced acidosis (P < 0.001). There was no relationship between the venous-arterial [HCO₃⁻] difference and arterial [H⁺] with exercise-induced acidosis or CBF; therefore, trans-cerebral [HCO₃⁻] exchange was unaltered throughout exercise when indexed against arterial [H⁺] or pH (P = 0.933 and P = 0.896, respectively). These results indicate that increases and decreases in systemic [HCO₃⁻] – during acute respiratory/exercise-induced metabolic acidosis, respectively – differentially affect cerebrovascular acid-base balance (via trans-cerebral [HCO₃⁻] exchange).