Objective To explore the therapeutic effects of hyperbaric oxygen on neonatal hypoxic - ischemic encephalopathy (HIE) and its potential mechanism. Methods The serum neuron specific enolase (NSE) were tested by ELISA and plasma endothlin (ET) were detected with radio - immune - assay (RIA) before and after hyperbaric oxygen therapy. Results The serum NSE and plasma ET were (14. 72 ± 4. 26)μg/L and (76. 1 ± 19. 2) ng/L in the moderate group respectively and (15. 64 ± 5. 82) μg/L and (82. 5 ± 21. 6) ng/L in the severe group respectively. The NSE and ET were increased significantly in the moderate group and the severe group as compared with the control group (12. 47 ± 3. 49 μg/L,56. 32 ± 16. 7 ng/L respectively); The NSE and ET were (13. 58 ± 4. 57) μg/L and (62. 4 ± 18. 5) ng/L. in the mild group respectively and not increased significantly with the control group. The level of NSE and ET significantly decreased after hyperbaric oxygen was engaged. Conclusions The serum NSE and plasma ET were a good discriminator for the evaluation of HIE, and its dynamic changes might be one of the potential mechanisms for the therapeutic effects of hyperbaric oxygen on HIE.