This exploratory study aims to determine whether the change in systolic blood pressure (sBP) after acute methylphenidate (MPH) administration (ΔBP) is associated with the neurocognitive response to MPH in the Conners Continuous Performance Test (CPT) in 513 children with ADHD (aged 6 to 12 years old). We noted that higher increases in sBP were associated with larger improvement in CPT performance with MPH. In the univariate regression model, the ΔBP accounted for an additional 2% of the variance in the change in CPT-Overall Index (OI) after controlling for covariates (p < .001). Linear regression analysis also indicated that ΔBP significantly contributed to predict a change in omission errors, reaction time, and reaction time variability (p < .001, p < .01, p = .001, respectively), but not in commission errors or detectability index (d`). Participants with a clinically meaningful sBP increase of at least 5 mmHg (n = 191) improved by 4.8 points on the CPT-OI score (p < .001), compared to an improvement of only 0.6 points for participants whose sBP declined by at least 5 mmHg (n = 121). In conclusion, larger sBP increases after MPH administration were associated with greater enhancement in CPT performance. These results could be useful in informing MPH dosing in clinical practice.