Current antidiabetic drugs have severe side effects, which may be minimized by new selective molecules that strongly inhibit α-glucosidase and weakly inhibit α-amylase. We have synthesized novel alkoxy-substituted xanthones and imidazole-substituted xanthones and have evaluated them for their in silico and in vitro α-glucosidase and α-amylase inhibition activity. Compounds6c, 6e, and9bpromoted higher α-glucosidase inhibition (IC50= 16.0, 12.8, and 4.0 µM, respectively) and lower α-amylase inhibition (IC50= 76.7, 68.1, and >200 µM, respectively) compared to acarbose (IC50= 306.7 µM for α-glucosidase and 20.0 µM for α-amylase). Contrarily, derivatives10cand10fshowed higher α-amylase inhibition (IC50= 5.4 and 8.7 µM, respectively) and lower α-glucosidase inhibition (IC50= 232.7 and 145.2 µM, respectively). According to the structure–activity relationship, attaching 4-bromobutoxy or 4′-chlorophenylacetophenone moieties to the 2-hydroxy group of xanthone provides higher α-glucosidase inhibition and lower α-amylase inhibition. In silico studies suggest that these scaffolds are key in the activity and interaction of xanthone derivatives. Enzymatic kinetics studies showed that6c,9b, and10care mainly mixed inhibitors on α-glucosidase and α-amylase. In addition, drug prediction and ADMET studies support that compounds6c,9b, and10care candidates with antidiabetic potential.