Network pharmacology and rat ischemia-reperfusion injury (MIRI) model was used to analyze the mechanism of cardiac protection by Trichosanthes. The animal experiments were approved by the Medical Ethics Committee of Wannan Medical College. Compounds were screened by TCMSP database and TCM Database@Taiwan according to oral bioavailability (OB > 30%) and drug like activity (DL > 0.18). The PDBID value of the compound (Z'-score < 0.5) was obtained in DRAR-CPI database and converted into a target protein by UniProt database. Human genes of target proteins were identified using the term "myocardial ischemia reperfusion injury" as the keyword through the CoolGeN database. GOTERM_BP _DIRECT enrichment analysis of target proteins related to MIRI and KEGG PATHWAY annotation analysis were performed using the DAVID database. The component-target protein-signal pathway network was constructed using Giphi0.9.2 software. The expression of mitogen-activated protein kinase (MAPK) signaling pathway-related proteins in MIRI rats pretreated with Trichosanthes (0.2, 1.0 and 2.0 g·kg^-1) was analyzed by Western blot with compound Danshen (85.05 mg·kg^-1) as a positive control. Network pharmacology found that 12 compounds, including schottenol in Trichosanthes, synergistically inhibit MIRI through multiple targets or biological pathways, involving target proteins such as extracellular regulated protein kinase 2 (ERK2), c-jun-N-terminal kinase-1 (JNK1) and p38MAPK in MAPK signaling pathways. Western blot results showed that phosphorylation of ERK1/2 was dose-dependently up-regulated in MIRI rats pretreated with Trichosanthes, while the level of p38MAPK or JNK1 phosphorylation was down-regulated in a dose-dependent manner. Compared with the control group, phosphorylation of ERK1/2, JNK1 and p38MAPK protein showed significant difference in medium and high dose groups (1.0 and 2.0 g·kg^-1) (P < 0.01). Therefore, Trichosanthes could play an anti-MIRI role by regulating phosphorylation of ERK1/2, JNK1 and p38MAPK proteins in rats. In conclusion, the targets and pathways of Trichosanthes on anti-MIRI were revealed by network pharmacology and verified in rat MIRI model, providing the scientific basis for further study on the mechanism of Trichosanthes for cardiac protection.