Multispectral photoacoustic (PA) imaging is a prime modality to monitor hemodynamics and changes in blood oxygenation (sO2). Although sO2 changes can be an indicator of brain activity both in normal and in pathological conditions, PA imaging of the brain has mainly focused on small animal models with lissencephalic brains. Therefore, the purpose of this work was to investigate the usefulness of multispectral PA imaging in assessing sO2 in a gyrencephalic brain. To this end, we continuously imaged a porcine brain as part of an open neurosurgical intervention with a handheld PA and ultrasonic (US) imaging system in vivo. Throughout the experiment, we varied respiratory oxygen and continuously measured arterial blood gases. The arterial blood oxygenation (SaO2) values derived by the blood gas analyzer were used as a reference to compare the performance of linear spectral unmixing algorithms in this scenario. According to our experiment, PA imaging can be used to monitor sO2 in the porcine cerebral cortex. While linear spectral unmixing algorithms are well-suited for detecting changes in oxygenation, there are limits with respect to the accurate quantification of sO2, especially in depth. Overall, we conclude that multispectral PA imaging can potentially be a valuable tool for change detection of sO2 in the cerebral cortex of a gyrencephalic brain. The spectral unmixing algorithms investigated in this work will be made publicly available as part of the open-source software platform Medical Imaging Interaction Toolkit (MITK).