A series of novel thiazolidine-2,4-dione or rhodanine derivatives (5a-5k, 6a-6k) were synthesized and evaluated for their α-glucosidase inhibitory activity. The majority of compounds exhibited potent inhibitory activity in the range of 5.44 ± 0.13 to 50.45 ± 0.39 μM, when compared to the standard drug acarbose (IC50 = 817.38 ± 6.27 μM). Among the compounds in the series, compounds 5k, 6a, 6b, 6e, 6h and 6k showed potent inhibitory potential with IC50 values of 20.95 ± 0.21, 16.11 ± 0.19, 7.72 ± 0.16, 7.91 ± 0.17, 6.59 ± 0.15 and 5.44 ± 0.13 μM, respectively. Compound 6k (IC50 = 5.44 ± 0.13 μM), containing chloro and rhodanine groups at the 2- and 4-positions of the phenyl ring respectively, was found to be the most active compound that inhibits α-glucosidase activity. Furthermore, molecular docking studies were performed to understand the binding interactions between the molecule and enzyme.