We have previously shown that selective inhibition of histone deacetylase 3 (HDAC3) decreases infarct volume and improves long-term functional outcomes after stroke. In this study, we examined the effects of HDAC3 inhibition on cerebral edema and blood-brain barrier (BBB) leakage and explored its underlying mechanisms. Adult male Wistar rats were subjected to 2-h middle cerebral artery occlusion (MCAO) and randomly treated i.p. with either vehicle or a selective HDAC3 inhibitor (RGFP966) at 2 and 24 h after stroke. Modified neurological severity scores (mNSS) were calculated at 2 h, 1 day, and 3 days. H&E, Evans blue dye (EBD) assay, and fluorescein isothiocyanate (FITC)-dextran were employed to assess cerebral edema and BBB leakage. Western blot for matrix metalloproteinase-9 (MMP9), MMP-9 zymography, and immunostaining for HDAC3, GFAP, Iba-1, albumin, aquaporin-4, claudin-5, ZO-1, and NF-kB were performed. Early RGFP966 administration decreased cerebral edema (p = 0.002) and BBB leakage, as measured by EBD assay, FITC-dextran, and albumin extravasation (p < 0.01). RGFP966 significantly increased tight junction proteins (claudin-5 and ZO-1) in the peri-infarct area. RGFP966 also significantly decreased HDAC3 in GFAP + astrocytes, which correlated with better mNSS (r = 0.67, p = 0.03) and decreased cerebral edema (r = 0.64, p = 0.04). RGFP966 decreased aquaporin-4 in GFAP + astrocytes (p = 0.002), as well as, the inflammatory markers Iba-1, NF-kB, and MMP9 in the ischemic brain (p < 0.05). Early HDAC3 inhibition decreases cerebral edema and BBB leakage. BBB protection by RGFP966 is mediated in part by the upregulation of tight junction proteins, downregulation of aquaporin-4 and HDAC3 in astrocytes, and decreased neuroinflammation.