Objective To explore the effects of chronic stress and stress cessation on hypothalamic appetite regulators in mice, and to explore the stress-dependent mechanism of appetite change. Methods A total of 32 male C57BL/6 mice were randomly divided into control (Ctrl) group (n＝16) and chronic unpredictable mild stress (CUMS) group (n＝16). The mice in the CUMS group were given CUMS to establish the stress model, and those in the Ctrl group were fed normally. The food intake and weight of mice were recorded. The CUMS model was verified through tail suspension experiments and forced swimming experiments. Eight mice in the Ctrl group and 8 mice in the CUMS group were randomly sacrificed at the 12th week. The Ctrl group was re-grouped into the cessation-control (C-Ctrl) group (n＝8), the CUMS group was re-grouped into the cessation-stress (C-CUMS) group (n＝8), and the mice were sacrificed at the 15th week. The mRNA and protein levels of appetite-regulating factors, including orexin 1 receptor (OX1R), leptin receptor (LEPR) and agouti-related protein (AgRP) in the hypothalamus, were detected by quantitative polymerase chain reaction and immunochemistry. Results From week 2 to week 11 of stress, the food intake of the mice in the CUMS group was significantly higher than that in the Ctrl group (all P＜0.05), while there was no significant difference in body weight between the 2 groups within 11 weeks (all P＞0.05). Compared with the Ctrl group, the immobility durations of forced swimming and tail suspension of the CUMS group were markedly longer after 11 weeks (both P＜0.01), indicating successful modeling. AgRP and OX1R mRNA expression in the hypothalamus of the CUMS group was significantly increased (both P＜0.01), while LEPR mRNA expression was significantly decreased (P＜0.01); AgRP protein in the hypothalamic arcuate nucleus of the CUMS group was significantly higher than that of the Ctrl group (P＜0.05), and LEPR protein was markedly lower than that of the Ctrl group (P＜0.01). However, after 3 weeks of stress cessation, the C-CUMS group had less food intake and lower body weight than the C-Ctrl group (both P＜0.05). The LEPR mRNA of the C-CUMS group was significantly increased (P＜0.01), while AgRP and OX1R mRNA were not significantly different (both P＞0.05). There was no significant difference in AgRP protein levels between the C-CUMS group and the C-Ctrl group (P＞0.05), while LEPR protein level of the C-CUMS group was significantly higher than that of the C-Ctrl group (P＜0.01). Conclusion CUMS can lead to increased appetite in mice, which may involve the functional regulation of LEPR and AgRP. After the stress cessation, the appetite decreases, which may involve the functional regulation of LEPR.