Matrine is a quinolizidine alkaloid derived from the herb Radix Sophorae Flavescentis, and possesses anti-oxidant, anti-inflammatory and anti-tumoral properties. However, its effectiveness against subarachnoid hemorrhage (SAH) is not well known. In this study, we investigated the effects of matrine on early brain injury (EBI) and the related potential mechanisms following SAH in rats. Our results showed that matrine pretreatment partially alleviated SAH-induced EBI, including neurological deficit, severity of SAH grade, brain edema, and blood-brain barrier (BBB) disruption in rats. In addition, SAH procedure induced BBB disruption with concomitant upregulation of MMP-9 expression and downregulation of tight junction proteins expression of BBB, namely, ZO-1 and occludin, which was partially reversed by matrine pretreatment. Matrine also reduced the increased levels of inflammatory cytokines TNF-α and IL-1β after the SAH operation. SAH induced neural cell apoptosis, as demonstrated by high apoptotic index and increased expression of Bax and caspase-3 proteins, as well as the reduced Bcl-2 expression, which were reversed by matrine pretreatment. Furthermore, matrine pretreatment partially suppressed SAH-induced Akt phosphorylation and IκB-α phosphorylation and degradation, and reduced NF-kB P65 protein levels. The expression of Keap1, Nrf2, and HO-1 proteins was distinctly enhanced in the SAH+matrine group, compared with the SAH+vehicle groups. Matrine pretreatment suppressed SAH-induced MMP-9 expression, which could be partially blocked by HO-1 inhibitor Sn-protoporphyrin IX (SnPP IX) but promoted by phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Our results suggest that matrine may alleviate EBI after experimental subarachnoid hemorrhage in rats possibly via PI3K/Akt-mediated NF-κB inhibition and Keap1/Nrf2-dependent HO-1 induction.