Background and Aims In general, physical activity (PA) and nonalcoholic fatty liver disease (NAFLD) have an inverse association. However, studies assessing the impact of the widely accepted Physical Activity Guidelines for Americans (PA Guidelines) on NAFLD are lacking. Approach and Results We performed a serial, cross‐sectional analysis among adults by using the 2007‐2016 US National Health and Nutrition Examination Survey. NAFLD and advanced fibrosis were defined by using various noninvasive panels. A PA questionnaire assessed the leisure‐time PA, occupation‐related PA, transportation‐related PA, and total sitting time as sedentary behavior. PA was categorized according to the PA Guidelines. Of the 24,588 individuals (mean age, 47.4 years; 47.9% males), leisure‐time PA (≥150 minutes per week) demonstrated 40% lower odds of NAFLD, whereas transportation‐related PA was associated with a 33% risk reduction in NAFLD. Analysis of total PA and sitting times simultaneously showed a dose‐response association between sitting time and NAFLD (P for trend < 0.001). Compliance with the PA Guidelines was lower in individuals with NAFLD versus those without NAFLD. The trends in compliance with the PA Guidelines for any type of PA remained stable in individuals with NAFLD except for a downtrend in transportation‐related PA. In contrast, an improvement in compliance with the PA Guidelines for leisure time was noted in the cohort without NAFLD. Although PA demonstrated a 10% stronger association with risk reduction of NAFLD in women, women showed a lower tendency of meeting the PA Guidelines. Trends in total sitting time increased significantly regardless of NAFLD status. Conclusions Sedentary behavior emerged as an independent predictor of NAFLD. Overall compliance with the PA Guidelines was lower in the cohort with NAFLD, with sex‐ and ethnicity‐based differences. Implementation of these observations in clinical practice may improve our understanding as well as clinical outcomes.