In this work, isatin was employed as the scaffold to design aldose reductase inhibitors with antioxidant activity. Most of the isatin derivatives were proved to be excellent in the inhibition of aldose reductase (ALR2) with IC 50 values at submicromolar level, and (E)-2-(5-(4-methoxystyryl)-2,3-dioxoindolin-1-yl) acetic acid (9g) was identified as the most effective with an IC 50 value of 0.015 μM. Moreover, compounds 9a-h with styryl side chains at the C5 position of isatin showed potent antioxidant activity. Particularly, the phenolic compound 9h demonstrated similar antioxidant activity with the well-known antioxidant Trolox. Structure-activity relationship and molecular docking studies showed that the acetic acid group at N1 and C5 p-hydroxystyryl side chain were the key structures to increase the aldose reductase inhibitory activity and antioxidant activity.