High-fat meals promote transient increases in proatherogenic factors, implicating the postprandial state in cardiovascular disease (CVD) progression. Although low-grade inflammation is associated with CVD, little research has assessed postprandial inflammation. Because of its anti-inflammatory properties, premeal exercise may counteract postprandial inflammation. The purpose of this study was to determine postprandial alterations in monocytes and circulating markers of endothelial stress and inflammation following a high-fat meal in young adults with or without premeal cycle exercise. Each subject completed two trials and was randomized to rest or cycle at a moderate intensity prior to eating a high-fat meal. Flow cytometry was used to assess monocyte cell surface receptor expression and concentration of endothelial microparticles (EMP). Plasma cytokines were assessed using Luminex MagPix. Statistical analysis was completed using separate linear mixed models analyses with first-order autoregressive (AR(1)) heterogeneous covariance structure. Significance was set at P ≤ 0.05. Percentage increases in classic monocyte CD11a and CD18 were greater overall in the postprandial period in the meal-only condition compared with the meal + exercise condition (P < 0.05). EMP concentration was 47% greater 3 h after the meal compared with premeal values in the meal-only condition (P < 0.05); no significant increase was observed in the meal + exercise condition. Premeal cycling blunted postprandial increases in EMP and CD11a and CD18. Acute, moderate-intensity exercise may help counteract possibly deleterious postprandial monocyte and endothelial cell activation.