Approximately 90% of people with diabetes mellitus (DM) are estimated to have type 2 diabetes (T2DM), which causes hepatic dysfunction. Pioglitazone is an antidiabetic medication that ameliorates diabetic liver dysfunction. Rosuvastatin is an antihyperlipidemic drug that alleviates the hepatic damage caused by T2DM. This study's objective was to look into the therapeutic potential of pioglitazone and rosuvastatin in combination in the management of diabetic liver injury induced by a high-fat diet (HFD) and streptozotocin (STZ). Forty male albino rats weighing 150 ± 15 g were used and split into five groups (8 rats in each). Groups II, III, IV, and V undergo induction of T2DM by feeding rats with HFD for 1 month and injecting a low dose of STZ. Group I, however, remained a negative control. Group II was not given any treatment; Group III was treated with pioglitazone; Group IV was treated with rosuvastatin; and Group V was treated with a combination of pioglitazone and rosuvastatin. After 28 days, serum liver enzyme levels and protein profiles were assessed. Expression of the inflammatory cytokines and Cytochrome P2E1 (CYP2E1) genes in the liver was also evaluated. Furthermore, hepatic tissue underwent histopathological examination. The results demonstrated considerable enhancement of the parameters under investigation in groups that were treated with pioglitazone, rosuvastatin alone, or their combination in comparison to the diabetic group. However, the effects of combined therapy are greater than those of monotherapy. In conclusion, concomitant administration of pioglitazone and rosuvastatin had greater potential for attenuating diabetic liver injury than monotherapy.