Background: The frankincense and myrrh can be used in traditional Chinese medicine (TCM) clinic with the treatment of stroke, while its mechanism is still unclear. The aim of this study was to investigate the effects of boswellic acid (BA) and myrrh sesquiterpene (MS) compositions on ischemic stroke in rats. Methods: The ischemic stroke rat model induced by ischemia-reperfusion (I/R) after transient middle cerebral artery occlusion (MCAO) was adopted and treated with boswellic acid and myrrh sesquiterpenes with proportions compatibility (BA-MS) of 10:1, 5:1 and 20:1. Biochemical indexes, histopathological analysis, metabolomics analysis of plasma and urine, as well as 16S rDNA sequencing of gut microbiota and short chain fatty acids were investigated. Results: BA and MS could obviously significantly ameliorated neurological deficits scores, reduced cerebral infarction area in I/R, and improve the damage of brains and lungs of MCAO rats. Additionally, it could significantly reduce the expression of neuroinflammatory factors (IL-1β, nNOS, BDNF, NGF) and angiogenic growth factors (ET-1, PAI-1, PDGF, VEGF, VWF), and significantly increase the expression of nerve indicators (TDP-43, NeuN) and angiogenic growth factors (Ang Ⅱ, TGF-β1, bFGF). After the administration of BA-MS, the metabolites of ischemic stroke in plasma and urine of ischemic stroke of rats were reversed, mainly correlated with the metabolic pathway of linoleic acid metabolism (impact value =1), and the gut microbiota and SCFAs metabolism of cecal contents were also improved. Conclusions: BA-MS can improve brain injury of MCAO rats via Ang/Tie and TLR4 signaling pathway, improve metabolism disorder by regulating linoleic acid metabolism pathway, and ameliorate gut microbes and their metabolic disorders.