A series of 4-thiazolidinone derivatives have been identified as hDHODH inhibitors. Several compounds exhibited moderate activities against hDHODH, especially compounds 26 and 31 with IC50 values of 1.75 and 1.12 μM, respectively. The SAR study and binding mode investigation demonstrate that the 4-thiazolidinone scaffold, the cyano substitution for R1, the ester structure for R2 and the hydrophobic substitutions at para- or meta-positions of the phenyl group for R are favorable for improving inhibitory activity. For this series of 4-thiazolidinone derivatives, the hydrogen bond with Tyr38 and the water-mediated hydrogen bond with Ala55 were proposed to be indispensable for maintaining the inhibitory activity against hDHODH. The presented SAR indicates that further decoration of the phenyl group at R may provide us more potent hDHODH inhibitors.