Adult male and female mosquitoes consume sugar as floral and extrafloral nectar. Earlier work demonstrated that mosquito populations and their vector potential are dependent upon the availability of sugar sources. Thus, a novel method of vector control may involve targeting sugar-feeding mosquitoes. Multiple human-safe sugar substitutes are already approved by the U.S. Food and Drug Administration and are readily available. However, plant-based sugar substitutes such as stevia (erythritol) have been shown to affect lifespan in other flies. Therefore, the current study was carried out to test the potential of commercially available sugar substitutes to adversely affect the survival, fecundity, and metabolism of adult Aedes aegypti mosquitoes. Of the four sugar substitutes tested, erythritol (Stevia), sucralose (Splenda), aspartame (Equal), and saccharin (Sweet’N Low), only erythritol negatively affected mosquito longevity and fecundity. The effect on fecundity was probably due in part to a corresponding decrease in glycogen and lipid levels over time in mosquitoes fed on erythritol. Comparative mosquito head transcriptomes indicated upregulation of a gene in the mannose biosynthesis pathway in females fed on erythritol, suggesting that N-linked glycosylation might be responsible for the negative impact of erythritol feeding in mosquitoes. Mosquitoes preferred sucrose when a choice was given but were not averse to erythritol. Our results suggest the possibility of using erythritol alone or in combination with sucrose as a component of attractive toxic sugar baits for a human-safe approach for mosquito control.