The combination of depression and anorexia may influence morbidity and progressive physical disability in the elderly. Gender differences exist in hypothalamic-pituitary-adrenal axis activation following stress exposure. The objective of this study was to investigate gender differences in feeding behavior under novelty stress in aged mice. Food intake measurement, immunohistochemical assessment, and mRNA expression analysis were conducted to investigate the role of serotonin 2C receptor (5-HT(2C)R) and its relationship with ghrelin in stress-induced suppression of feeding behavior in aged mice. After exposure to novelty stress, a 21-fold increase in plasma corticosterone and remarkable suppression of food intake were observed in aged male mice. Furthermore, a 5-HT(2C)R agonist suppressed food intake in aged male mice. Novelty stress induced a 7-fold increase in 5-HT(2C)R and c-Fos co-expressing cells in the paraventricular nucleus of the hypothalamus in aged male mice but caused no change in aged female mice. Plasma acylated ghrelin levels decreased in stressed aged male mice and administration of the 5-HT(2C)R antagonist inhibited this decrease. The 5-HT(2C)R antagonist also reversed the suppression of food intake in estrogen receptor α agonist-treated aged male mice. Therefore, conspicuously suppressed feeding behavior in novelty stress-exposed aged male mice may be mediated by 5-HT(2C)R hypersensitivity, leading to hypoghrelinemia. The hypersensitivity may partly be due to estrogen receptor activation in aged male mice.