Background We aimed to evaluate possible intracranial pressure (ICP) changes caused by screw activations during active microimplant-assisted rapid palatal expansion (MARPE) therapy of post-pubertal individuals by measuring the optic nerve sheath diameter (ONSD) under ultrasonography (US) guidance. Methods This study’s participants comprised 15 patients (7 males, 8 females) with posterior crossbite and a mean age of 16.7 years (14.25–20.08 years). The Maxillary Skeletal Expander (MSE) appliance was used to perform MARPE in all patients. Their vital signs (heart rate, mean arterial pressure (MAP), and peripheral oxygen saturation (SpO2)) were recorded. The ONSD was measured by US immediately before the first screw activation (T0), and the measurements were repeated 1 min (T1) and 10 min (T2) after the first activation. In the last session of active MARPE therapy, the same measurement protocol was performed as in the first activation session (T3, T4, and T5). The patients’ perceptions of pain during the screw activation were also noted at T1 and T4 using a four-category verbal rating scale (VRS-4). The significant differences among different time intervals performed with the Friedman test (for all tested variables; SpO2, MAP, Heart Rate, VRS-4 and ONSD). Spearman correlation test was used for VRS-4 and ONSD comparisons. The statistical significance level was accepted as p < 0.05. Results The ONSD values ​​(T1 and T4) relatively increased within 1 min after screw activation but did not reach a statistically significant level (p > 0.05). There was also no significant difference between the initial (T0) and the final (T5) ONSD values ​​during the active MARPE therapy (p > 0.05). Conclusion There is no changes or alterations in intracranial pressure in late adolescents during active MARPE therapy.