Cisplatin is a chemotherapeutic agent, but its clinical use is limited by dose-dependent nephrotoxicity. This study investigated whether shikonin could attenuate cisplatin-induced renal injury without compromising its antitumor activity in an MDA-MB-231 xenograft  model. Mice were assigned to control, shikonin, cisplatin, or cisplatin plus shikonin groups. Cisplatin (6 mg/kg) was administered on day 1, and shikonin (6 mg/kg) on days 2–6; this cycle was repeated for 4 weeks. Antitumor efficacy was assessed by tumor growth and Ki-67 expression; nephrotoxicity by renal injury biomarkers, serum biochemical parameters, apoptosis- and oxidative stress-related proteins, and histopathological examination. Cisplatin inhibited tumor growth, while shikonin coadministration maintained comparable tumor suppression. Cisplatin increased urinary and renal tissue injury biomarkers and altered the expression of apoptosis- and oxidative stress-related proteins. These changes were attenuated by shikonin coadministration. Serum biochemical parameters remained within normal ranges, but showed mild renal injury trends. Histopathological examination revealed the most pronounced kidney and liver damage in the cisplatin group, and less severe tissue injury in the combination group. Tumoral Ki-67 expression was similarly reduced in the cisplatin and combination groups. These findings suggest shikonin reduces cisplatin nephrotoxicity via apoptosis/oxidative stress while preserving antitumor efficacy.