The yellow drum (Nibea albiflora) is an economically important maricultured fish in China, but the aquaculture of this species has recently been limited by an increase in overwinter mortalities associated with cold and starvation stress due to global climate changes. To better understand the interaction between starvation and cold-stress-driven overwinter mortality, we investigated the effects of these stresses on the growth performance, liver lesions, and immune response of yellow drum fish. The fish were subjected to different cold treatments and under starvation stress. The experiment lasted 30 days and involved four experimental groups: a fed group and a fasted group maintained at 16 °C (control), and a fed group and a fasted group subjected to cold stress at 8 °C. We found that the growth of yellow drum was severely affected by cold temperatures and starvation. Throughout the experimental period, the body weights were significantly lower in the groups subjected to starvation and cold stress than in the control group. The liver cells showed irregular shapes and disorderly arrangements in the stress groups; indicating liver lesions. The gene expressions of antioxidant enzymes (copper, zinc superoxide dismutase, manganese superoxide dismutase, iron superoxide dismutase, and catalase) in the liver were lower in the groups subjected to starvation and cold stress than in the control groups. These results were basically consistent with the enzyme activities of superoxide dismutase and catalase tested in the livers. In addition, activities of immunomodulatory enzymes (alkaline phosphatase and acid phosphatase) were also inhibited in groups subjected to stress throughout the experiment period. These findings suggested that starvation and cold stress inhibited growth, depressed liver function, and suppressed the immune system of yellow drum, which likely would lead to physiological failure and increased susceptibility to infection. The present study offers insights into the physiological and immune response of yellow drum under cold and starvation stress. These insights not only provide baseline information from which effective strategies can be established and appropriate management decisions formulated, but can also be used to improve the overwinter survival of this important fish species in China.