Some types of per- and poly-fluoroalkyl substances (PFAS) have been banned over the last two decades, but millions of Americans continue to have exposure to the compounds through drinking water and consumer products. Therefore, understanding the changes in serum PFAS concentrations after their limited use is necessary to protect public health. In this study, we evaluated trends of serum PFAS compounds (PFOS, PFOA, PFHxS, PFDA, and PFNA) to determine their distribution among the United States general population. We analyzed serum concentrations of PFAS measured from random subsamples of the National Health and Nutrition Examination Survey (NHANES) participants. The study results demonstrated that demographic factors such as race/ethnicity, age, and sex may influence the levels of serum PFAS over time. Adults, males, Asians, Non-Hispanic Blacks, and Non-Hispanic Whites had high risks of exposure to the selected PFAS. Overall, serum PFAS levels declined continuously in the studied population from 1999 to 2018. Among the studied population, PFOS and PFDA were the most and least prevalent PFAS in blood serum, respectively. Serum levels of PFDA, PFOA, and PFHxS showed upward trends in at least one racial/ethnic group after 2016, which underscores the need for continuous biomonitoring of PFAS levels in humans and the environment.