Background: Coffee is one of the most popular beverages globally and contains several bioactive compounds that are relevant to human health. Many nutritional strategies modulate sirtuin-1, thereby impacting aging and cardiometabolic health. This study investigated the influence of different blended coffees on serum sirtuin-1, blood lipids, and plasma homocysteine. Methods: An eight-week randomized clinical trial that included 53 healthy adults of both sexes analyzed the effects of daily intake of 450 to 600 mL of pure Arabica or blended (Arabica + Robusta) coffee intake of filtered coffee on blood sirtuin-1, lipids, and homocysteine. Results: Both Arabica and blended coffees similarly increased serum sirtuin-1 concentration, from 0.51 to 0.58 ng/mL (p = 0.004) and from 0.40 to 0.49 ng/mL (p = 0.003), respectively, without changing plasma homocysteine, folic acid, glucose, and CRP. However, the blended coffee intake increased total cholesterol from 4.70 to 5.17 mmol/L (p < 0.001) and LDL-cholesterol from 2.98 to 3.32 mmol/L (p < 0.001), as well as HDL-c from 1.26 to 1.36 mmol/L (p < 0.001). Conclusion: Both coffee powders increased sirtuin-1 expression, but our results suggest that blended coffee had hypercholesterolemic effects which could increase cardiovascular risk. Therefore, preference should be given to Arabica coffee for the best cardiometabolic benefits of coffee.