Diabetes mellitus (DM) is strongly associated with depression, especially in women. This study was designed to investigate the gender-specific association between DM and depressive mood by family history of diabetes. Data from the Korea National Health and Nutrition Examination Survey, a population-based cross-sectional survey in 2020, were used. Of 6,133 participants aged 19 years or older, 4,259 participants were included after excluding participants without data of laboratory or physical examination, medical or family history of diseases, or depression scores of Patient Health Questionnaire-9. We examined associations of glucose and insulin metabolism, and DM with depressed mood by sex and family history of diabetes using logistic regression analyses with three stepwise models. In men, fasting glucose and HbA1c (odds ratio [OR]: 1.25, 95% confidence interval [CI]: [1.10, 1.42]) levels were significantly associated with depressed mood. Men with DM and a family history of diabetes were also significantly associated with depressed mood (OR: 1.84, 95% CI: [1.12, 3.05]), whereas DM without a family history showed no association. In women, glucose and insulin metabolism had no associations with depressed mood, and DM was also not associated with depressed mood regardless of a family history of diabetes. In Korean adults, DM with a family history of diabetes and glucose metabolism showed significant associations with depressed mood in men, but not in women. Our results suggest that men with both DM and a family history of diabetes should be paid more attention to depressed moods, considering ethnic characteristics.