Background: Previous studies have not examined whether depression risk in vitiligo patients varies across racial and ethnic groups in large, diverse populations like the U.S., limiting our understanding of differential mental health outcomes among dermatology patients. Objective: To assess the risk of depression in patients with vitiligo compared to those without vitiligo, and to analyze differences across racial and ethnic subgroups. Methods: We conducted a retrospective case-control study using electronic health record data from the NIH All of Us Program (2018–2024). Adjusted odds ratios (aOR) determined the risk of vitiligo and depression. Subgroup analyses included Asian, Black, White, Hispanic, and Non-Hispanic populations. Results: Vitiligo was associated with increased relative risk of depression (aOR, 1.34; 95% CI, 1.16–1.54). The highest risk was observed in Black (2.13, 1.55–2.91) and Hispanic (1.45, 1.09–1.94) patients. Non-Hispanic patients also showed elevated risk (1.29, 1.09–1.52). Risk was nonsignificant in White (1.06, 0.85-1.29) and Asian (0.704, 0.15- 2.38) patients. Limitations: Our study uses categorical race and ethnicity classifications. Conclusion: Vitiligo is associated with an increased risk of depression, particularly among Black and Hispanic individuals, underscoring the importance of tailored approaches to dermatologic and mental health care.