Baicalin (BA), a multi-target neuroprotective agent, has poor solubility resulting in low bioavailability. In this study, multidrug-loaded liposomes were prepared by encapsulating BA, borneol (BO) and cholic acid (CA) to prevent ischemic stroke. BBC-LP were administered intranasally (i.n.) to deliver into the brain for neuroprotection. Finally, potential mechanism of BBC treating ischemic stroke (IS) was explored by network pharmacology. In this study, BBC-LP was prepared by reverse evaporation method, and the encapsulation efficiency (EE) of the optimized liposomes was 42.69% and the drug loading (DL) was 6.17%. The liposomes had low mean particle size (156.62 ± 2.96 nm), polydispersity index (PDI) (0.195) and zeta potential (−0.99 mv). Compared to BBC, pharmacodynamic studies revealed that BBC-LP significantly improved neurological deficits, brain infarct volume, and cerebral pathology in MCAO rats. Toxicity studies showed that BBC-LP was not irritating to the nasal mucosa. These results suggest that BBC-LP can safely and effectively ameliorate IS injury by i.n. administration. Moreover, it's neuroprotective function may be related to the anti-apoptotic and anti-inflammatory effects exerted by phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway and mitogen-activated protein kinase (MAPK) signaling pathway.