Cardiovascular disease (CVD) is the global leading cause of death; however, multiple cardiovascular and metabolic risk factors for CVD can be modulated through alterations in diet. Cottonseed oil (CSO), an oil rich in polyunsaturated fats, has been shown to elicit improvements in lipid profiles, appetite control, and metabolic responses in young healthy adults; yet, it has never been assessed in adults with hypercholesterolemia. Further, human CSO consumption has never been assessed for a period longer than seven days. The objective of this study was to compare effects of CSO vs. olive oil (OO; a well-characterized “healthy” oil rich in monounsaturated fats) diet enrichment on cardiometabolic health markers including blood lipids, angiopoietin-like proteins (ANGPTL), appetite control, metabolism, inflammatory cytokines, and markers of coagulation potential in adults with hypercholesterolemia. We conducted an 8-week partial outpatient feeding trial, where participants were randomized to either CSO or OO diet interventions. During the 8-week diet interventions, participants received prepared foods that provided approximately 60% of their daily energy needs. The provided intervention foods delivered approximately 30% of participant energy needs as the assigned intervention oil (CSO or OO). In manuscript #1 (chapter #3), fasting lipid profiles including total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B were improved with CSO compared to OO diets. Furthermore, in manuscript #1 (chapter #3) postprandial lipemia and glycemic control were worse after OO compared to CSO enrichment. In manuscript #2 (chapter #4) postprandial ANGPTL-3 and -4 worsened with OO vs. CSO diets. In manuscript #3 (chapter #5), there were no differences in substrate utilization at fasting or postprandially; however, OO led to a greater increase in diet induced thermogenesis compared to CSO. Conversely, manuscript #4 (chapter #6) shows greater improvements in appetite measures (fasting cholecystokinin, postprandial ghrelin, postprandial fullness, and suppression of energy intake) with CSO vs. OO diet enrichment. In manuscript #5 (chapter 7), there were no changes observed in fasting markers of inflammation or coagulation potential. Taken together, these results show daily CSO consumption to elicit greater improvement on markers of cardiometabolic health in adults with hypercholesterolemia compared to daily OO consumption.