High-altitude disease (HAD) describes the failure to adapt to the lack of oxygen found at high altitudes and therapeutic antioxidant effects have been attributed to pomegranate peel (PP) extract. Network pharmacology, molecular docking, and experimental validation were used to study mechanisms responsible for the alleviation of HAD by PP. The aim was to establish a reference for future research and aid technological development, particularly in clinical settings. Network pharmacology analysis showed that PP affected many targets in HAD via the active ingredients, luteolin 7-O-glycoside, punicalagin, and ellagic acid. HNRNPA1, HSPA1B, HSPA1A, CUL4B, CLTC, PPP1CA, PARP1, RACK1, NEDD8, and MAP3K1 were all targets, responsible for effects on ribosomes, apoptosis, cell cycle, mRNA surveillance pathway, and the MAPK signaling pathway. PP had an antiapoptosis effect on H9c2 cells damaged by hypoxia, as shown by annexinV-FITC/PI double staining. Practical Applications. HAD comprises a group of diseases caused by failure to adapt to a low-oxygen environment. PP extract has previously been shown to have antioxidant effects. PP attenuated damage to H9c2 cells and reduced the apoptosis rate. The current results lay the foundation for further experimental investigations.