Background: Exposure to air pollution is a leading cause of global mortality. Volatile organic compounds (VOCs) are constituents of ambient air that could exert adverse health effects. Objective: To examine the relationship between VOC levels in ambient air and individual-level exposure to VOCs, as assessed by urinary VOC metabolites. Methods: Secular trends in 11 ambient air VOCs (2005–2013) and individual-level metabolites of 14 VOCs (2005–2014) were assessed using National Monitoring Programs (NMP) and National Health and Nutrition Examination Survey (NHANES) data, respectively. To isolate environmental exposure, individuals reporting exposure to tobacco smoke were excluded. Quantile regression models were used to assess secular trends in VOC exposure, and survey-weighted regression models were built to identify factors associated with VOC exposure. Results: All annual levels of ambient VOCs decreased from 2005 to 2013 (Range: 12.5%–77.2%). However, 11 of the corresponding VOC metabolites increased during the same time (Range: 0.3%–53.6%). There was a proportional change in patterns of VOC exposure across NHANES waves, with the middle quantiles of exposure showing the largest increase. VOC exposures were significantly associated with age, sex, race, education, and physical inactivity, but not with secular VOC trends. Discussion: In the United States, individual-level exposure to several VOCs increased between 2005 and 2014 despite a decline in ambient air VOC levels. This inverse relationship suggests that ambient VOCs are not the primary source of VOC exposure, therefore, decreasing ambient VOCs alone may not be sufficient to protect against the adverse health effects associated with VOC exposure.