Stroke is one of the most important cause of death and disability, especially when considering the increasing life expectancy worldwide, with ischemic stroke being much more common than hemorrhages. In the physiopathological chain of ischemic stroke, brain edema is one first element that if attended to might reduce tissue necrosis, penumbra, and increase functional recovery. Aquaporin 4 (AQP4) has been found to be the most important water channel in the brain, and its inhibition before inducing focal ischemia in an animal model of stroke proved to alleviate the pathology and improve clinical recovery. In this study, we have treated a rat model of ischemic stroke with the AQP4 inhibitor TGN-020 after inducing the lesion, and performed for the first time a direct histopathological evaluation of the brain and infarct's volume. Besides utilizing immunohistochemistry targeting the growth-associated protein-43 (GAP-43) in order to delineate the infarct regions, we have used the Cavalieri's principle of tissue volume measurements starting form seriate sections, and for the first time in neuropathology, we have utilized a high-resolution object scanner to assess global brain volume changes. Our results showed that TGN-020 clearly reduces infarct volume in TGN-020 treated animals compared to untreated animals, as well as the volume of the brain hemispheres. Although reduced, the effect was also present in the contralateral hemisphere. Given these data, a more in-depth characterization of the histopathological and molecular changes induced by AQP-4 are needed for considering it as a bona fide treatment option.