Thiazolidinediones are insulin-sensitizing agents that working by binding to PPAR-c, which leads to alteration in the expression of key regulators of lipid homeostasis, glucoregulatory, and insulin resistance genes. In this study, we investigated the effects of treatment with the benzylidene thiazolidinedione (BTZD) derivatives; (5Z)-5-(4-chlorobenzylidene)-3-(4-methyl-benzyl)-thiazolidine-2,4-dione (1), (5Z)-5-(4-methoxy-benzylidene)-3-(4-methyl-benzyl)-thiazolidine-2,4-dione (2), (5Z)-5-(2,4-dimethoxy-benzylidene)-3-(4-methyl-benzyl)-thiazolidine-2,4-dione (3), and (5Z)-5-(4-dimethylamino-benzylidene)-3-(4-methyl-benzyl) thiazolidine-2,4-dione (4) on insulin resistance associated with hyperinsulinemia, hyperglycemia, and hyperlipidemia in high-fat diet induced mice. Body weight, serum triglyceride and total cholesterol, aspartate aminotransferase (AST), alanine aminotransferase (ALT), fasting serum glucose (FSG), and fasting serum insulin levels (FSI) of all groups were assayed. The insulin resistance indices were calculated using the homeostasis model assessment (HOMA-IR). None of the treatments caused any significant alteration in body weight. The elevated serum triglyceride, total cholesterol, FSG and FSI levels were reduced significantly (P<0.01) by BTZDs and rosiglitazone, in comparison with the control (HFD-C) group. Compound (2) was 34% more potent than rosiglitazone in terms of decreasing insulin levels (P<0.05). HOMA-IR indices of BTZDs and rosiglitazone-treated groups were significantly (P<0.01) improved when compared to the HFD-C group. Moreover, only the derivatives (1) and (2), were able to reduce the serum AST levels when compared with the HFD-C group. This study suggests that these BTZDs derivatives not only reduce insulin resistance in high-fat fed mice, but also ameliorate associated hyperinsulinemia, hyperglycemia, and hyperlipidemia. Additionally, none of the derivatives exerted any major adverse effect on liver transaminases or body weight.