Xanthones are oxygen-containing heterocyclic compounds that exhibit a wide range of biological and pharmacological properties. Some natural and synthetic derivatives have been identified for their antidiabetic profile, mainly as α-glucosidase inhibitors. However, studies concerning the inhibition of both carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase are scarce. Thus, in order to identify some of these dual-target antidiabetic agents, a series of new synthetic xanthones were evaluated together with their commercial parents mangiferin (4), α-mangostin (5) and γ-mangostin (6). The results showed that xanthones exhibited a systematic stronger inhibition against α-glucosidase rather than for α-amylase. Derivatives 2c, 3a and 3b, bearing one catechol moiety, were the most active inhibitors of α-amylase, while xanthones 2c, 3b and 3c were the most active against α-glucosidase activity, with IC50 values lower than 10 μM. These findings suggest that the substitution pattern of the xanthone scaffold modulated the inhibitory activity of these compounds, and some structure-activity relationships could be established for both assays. In addition, the type of inhibition was also studied, and the results indicate a competitive type of inhibition for α-amylase activity by xanthones 2c, 3b, 3c and γ-mangostin (6). On the other hand, non-competitive inhibition mechanisms can be ascribed for all xanthones 1-6 against α-glucosidase. The present work can open a promising area of research based on the design of novel xanthone derivatives, based on natural ones, for targeting key enzymes involved in glucose metabolism and therefore in the management of type 2 diabetes mellitus.