This study examined whether the association between obesity and non-specific mental distress has become stronger among the working-age population over time and whether a change in the association was moderated by particular socioeconomic characteristics. More than two million adults aged 20-55, from 1993 to 2010 (except for 2002), were analyzed using self-reported Mentally Unhealthy Days (a measure of non-specific mental distress) and Body Mass Index (BMI) from the Behavioral Risk Factor Surveillance System annual survey. This study found that prevalence of obesity more than doubled (p < 0.01) from 14.0% in 1993 to 28.6% in 2010 and Mentally Unhealthy Days increased 20% (p < 0.01) from 3.17 to 3.88 during the same period. Adults with obesity (BMI ≥ 30) experienced around 0.32 (p < 0.05) more Mentally Unhealthy Days than their counterparts without obesity in 1993, but the difference increased to 1.09 (p < 0.05) in 2010. An increase in the association was much larger for women, Whites, adults aged 36-45, low-income earners, and individuals with some college education. Quantifying the magnitude of the association provides policymakers and researchers with valuable information towards developing and evaluating obesity prevention programs and mental health enhancement policies.