Psychological distress is commonly reported in patients with advanced cancer. Family is considered a psychological supporter for patients during their cancer journey. This study aimed to examine the effect of a nurse-led family involvement program on anxiety and depression in patients with advanced hepatocellular cancer. This is a quasi-experimental study with a two-group, pre-post-test design. Forty-eight participants were recruited at a male medical ward in a university hospital in Southern Thailand, and assigned to either the experimental or the control group. The experimental group received the nurse-led family involvement program, while the control group received only conventional care. Instruments included a demographic data form, clinical data form, and the Hospital Anxiety and Depression Scale. Data analyses were performed using descriptive statistics, chi-square, Fisher's exact test, and t-test. The results revealed that the mean scores of anxiety and depression in the experimental group at post-test were significantly lower than on the pretest and significantly lower than those of the control group. The results indicate that a nurse-led family involvement program has a short-term effect on the reduction of anxiety and depression in male patients with advanced HCC. The program can be useful for nurses to encourage family caregivers to engage in patient care during hospitalization.