What environmental factors contribute to seasonal variation in immune function in striped hamsters (Cricetulus barabensis) remains unclear. How immune responses would respond to natural seasonal changes in photoperiod and temperature was investigated in the present study. Twenty-nine male and 30 female hamsters were randomly assigned to the winter, spring, summer, and autumn groups. Spleen mass was the highest in male hamsters during autumn, while it did not differ among seasons in females. Regardless of sex, bacteria killing activity (BKA) was the lowest in the spring, whereas phytohaemagglutinin (PHA) responses at 12 h, 24 h, and 48 h were all highest in the winter among the four seasons. Females had the lowest titers of immunoglobin (Ig)G5, 10, and 15 in winter, while they did not show seasonal variation in males. Compared with male hamsters, females had higher levels of IgG10 and IgG15 in the spring and autumn, but had lower BKA in autumn. Blood glucose was the lowest in the spring in both sexes. Males had higher leptin level in winter than in summer and autumn, while leptin level was higher in winter and spring than in autumn in females. Corticosterone level was higher in winter and summer than in spring and autumn in males, while it was higher in winter than in the other three seasons in females. Males had higher levels of leptin in winter, and corticosterone in summer, than females. In summary, distinct parts of the immune system respond differently to natural seasonal variations in photoperiod and temperature.