This study aimed to elucidate whether melatonin would exert beneficial effects on the neuronal functions of the nodose ganglion (NG) following acute hypoxic insult. The cytochrome oxidase (COX) and the nicotinamine adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry along with the nitric oxide synthase (NOS) immunofluorescence were used to examine the metabolic stage and nitric oxide production in nodose neurons respectively. Adult rats were injected intraperitoneally with melatonin at 5 or 100 mg/kg. Hypoxia was achieved by placing the rats into an altitude chamber (PO2 = 43 torr) for 4 hr. The results show that in normal untreated rats, nearly all and about 43% of the NG neurons displayed COX and NOS/NADPH-d reactivities with various staining intensities respectively. However, COX reactivity was drastically decreased while NOS/NADPH-d reactivity was significantly upregulated following hypoxia treatment. In melatonin pretreated rats, the hypoxia-induced reduction of COX reactivity was obviously prevented and the augmentation of NOS/NADPH-d reactivity was successfully suppressed. The deficit in the metabolic stage and the over-activation of NOS would contribute to the generation of oxidative stress. By effectively preventing the metabolic disruption, melatonin may have potential utility in therapeutic treatment of neuronal dysfunctions where oxidative stress is a participant.