Obesity is a major public health problem both globally and within the U.S. It varies by multiple factors, including but not limited to income and sex. After controlling for potential covariates, there is little evidence to determine the association between income and obesity and how obesity may be moderated by sex and family income. We examined the association between income and obesity in U.S. adults aged 20 years and older, and tested whether this relationship differs by race or ethnicity groups. For this analysis, we used data from the 1999–2016 National Health and Nutrition Examination Surveys (NHANES). Obesity was determined using Body Mass Index ≥ 30 kg/m2; the Gini coefficient (GC) was calculated to measure income inequality using the Poverty Income Ratio (PIR). We categorized the PIR into five quintiles to examine the relationship between income inequality and obesity. For the first set of analyses, we used a modified Poisson regression in a sample of 36,665 adults, with an almost equal number of men and women (women’s ratio was 50.6%), including 17,303 white non-Hispanics (WNH), 7475 black non-Hispanics (BNHs), and 6281 Mexican Americans. The models included age, racial/ethnic groups, marital status, education, health behaviors (smoking and drinking status and physical activities), health insurance coverage, self-reported health, and household structure (live alone and size of household). Adjusting for potential confounders, our findings showed that the association between PIR and obesity was positive and significant more frequently among WNH and BNH in middle and top PIR quintiles than among lower-PIR quintiles; this association was not significant in Mexican Americans (MAs). Results of GC in obese women showed that in comparison with WNHs (GC: 0.34, S.E.: 0.002), BNHs (GC: 0.38, S.E.: 0.004) and MAs (GC: 0.41, S.E.: 0.006) experienced higher income inequality, and that BNH obese men experienced the highest income inequality (GC: 0.45, S.E.: 0.011). The association between PIR and obesity was significant among WNHs and BNHs men in the 3rd, 4th and 5th PIR quintiles. The same association was not found for women. In treating obesity, policymakers should consider not only race/ethnicity and sex, but also strategies to reduce inequality in income.