Background: Ketamine is famous for its dissociative anesthetic properties. It is also analgesic, anti-inflammatory and anti-depressant, and even has a cerebral protective effect. We searched the evidence of the correlation between ketamine target and clinical efficacy and utilized network pharmacology to gather information about the multi-target mechanism of ketamine against cerebral ischemia (CI). We found that ketamine's clinical significance may be more extensive than previously thought. Methods: The drug target of ketamine and CI-related genes were predicted by SwissTargetPrediction, DrugBank, PubChem, GeneCards and DisGeNET databases. The intersection of ketamine's drug-targets and CI-related genes was analyzed by using GO and KEGG. We predicted the molecular docking between the potential target and ketamine. Results: The results indicated that the effect of ketamine on CI was primarily associated with the target of a-synuclein (SNCA), muscarinic acetylcholine receptor Ml (CHRM1) and nitric oxide synthase 1 (NOS1). It principally regulates the signal pathways of circadian transmission, calcium signaling pathway, dopaminergic synapse, cholinergic synapse and glutamatergic synapse. Molecular docking analysis exhibited that hydrogen bond and Pi-Pi interaction were the predominant modes of interaction. Conclusion: There are protein targets affected by ketamine in the treatment of CI. Three pivotal targets involving 298 proteins, SNCA, CHRM1 and NOS1, have emerged as multi-target mechanisms for ketamine in CI therapy. Similarly, this study also provides a new idea for introducing network pharmacology into the evaluation of multi-targeted drugs for CI and cerebral protection.