Background: In the last few years there has been emerging interest in substituting added sugars from juices with other sweeteners to make them healthier. But their long-term effects have been poorly evaluated. The aim of this study is to evaluate the effect of the addition of stevia, sucralose and sucrose (control) to maqui-citrus beverages on antioxidant and inflammatory status. Methods: a 3-arm parallel, randomized and triple blind clinical trial was performed in overweight subjects (n = 138), who consumed the test beverage (330 mL day-1) for 60 days. The following markers were determined: antioxidant status (ORAC, homocysteine, and oxidized LDL), safety parameters (ALP, AST, ALT, and total bilirubin), lipid profile (total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides) and inflammatory biomarkers (IL-6, TNF-α, and IL-10). Results: The homocysteine levels significantly increased after consumption of sucralose (27%, p = 0.001) and sucrose (40%, p = 0.006). A significant increase in the IL-10 concentration after consumption of the stevia sweetened beverage, and in ORAC values (21%) in subjects with lower basal antioxidant status were observed. The HDL and total cholesterol levels significantly increased after consumption of sucralose (p = 0.039) and sucrose (p = 0.001), respectively. No changes in triglycerides, LDL or oxidized LDL were observed. Conclusions: Oxidative stress and an inflammatory response were observed after consumption of these sweetened beverages, with the exception of stevia, which produced an anti-inflammatory response. The possible antioxidative effects of this polyphenol-rich beverage may only benefit those individuals with poorer antioxidant status. Many randomized controlled trials at normal levels of consumption using commonly consumed sweeteners are necessary to clarify their roles in health.