This study investigated the protective effects of carvedilol alone and coadministered with prednisolone and diltiazem on doxorubicin (DOX) and 5‐fluorouracil (5‐FU)‐induced toxicity. Each of 2 pools of 70 female rats were randomly allotted into 10 groups of 7 animals each and treated as follows: Group 1: normal saline (10 mL/kg); Group 2: normal saline and DOX (40 mg/kg)/5‐FU (20 mg/kg) alone; Group 3: gallic acid (200 mg/kg) and DOX/5‐FU; Group 4: carvedilol (0.075 mg/kg) and DOX/5‐FU; Group 5: carvedilol (0.15 mg/kg) and DOX/5‐FU; Group 6: carvedilol (0.30 mg/kg) and DOX/5‐FU; Group 7: diltiazem (3.43 mg/kg) and DOX/5‐FU; Group 8: diltiazem (3.43 mg/kg), carvedilol (0.15 mg/kg), and DOX/5‐FU; Group 9: prednisolone (0.57 mg/kg) and DOX/5‐FU; and Group 10: prednisolone (0.57 mg/kg), carvedilol (0.15 mg/kg), and DOX/5‐FU. Treatments were done p.o. for 16/14 days for the DOX/5‐FU models. DOX/5‐FU was administered i.p. to the rats in Groups 2‐10 on day 14/10‐14. On day 17/15 (DOX/5‐FU), blood samples were collected, and liver and kidneys of rats were harvested for antioxidant and histopathological assessments. Carvedilol alone and coadministered with prednisolone significantly (P < .05) decreased alanine aminotransferase level compared with administration of DOX alone. Carvedilol alone and coadministered with diltiazem significantly (P < .05) decreased creatinine level compared with administration of DOX/5‐FU alone. Carvedilol alone and coadministered with diltiazem and prednisolone significantly (P < .05) increased the level of hepatic superoxide dismutase and catalase, and decreased malondialdehyde compared with DOX administration alone. Histopathological observations correlated with results of biochemical and antioxidant analyses. Carvedilol administered alone and coadministered with diltiazem and prednisolone reduced the effect of DOX/5‐FU‐induced hepatic and renal toxicities due to enhanced in vivo antioxidant activity. The protective effect was more prominent in the doxorubicin model compared with the 5‐fluorouracil test. Coadministration of carvedilol with either diltiazem or prednisolone did not show better protection relative to carvedilol alone.