Background Chemotherapeutic agents, with or without other drugs and radiation, may cause indirect or direct hepatotoxicity. Doxorubicin-induced hepatotoxicity (DIH) is a major health concern in cancer patients receiving this cytotoxic drug that is mostly resulted from the production of reactive oxygen species leading to transient or permanent liver damages. Silymarin, a flavonoid extracted from the Silybum marianum, exhibits antioxidant and anti-inflammatory activities. Purpose This study aimed to investigate the clinical efficacy of systemic administration of silymarin in management of chemotherapy induced hepatotoxicity in patients with non-metastatic breast cancer who received doxorubicin/cyclophosphamide-paclitaxel (AC-T) regimen. Material: In this randomized, triple blind, placebo-controlled clinical trial, 30 patients who received AC-T who fulfilled the inclusion criteria were randomly allocated to silymarin (n = 15) or placebo (n = 15) groups to receive oral silymarin 140 mg three times a day or placebo tablets, respectively. Fatty liver severity was assessed by liver ultrasound imaging and FibroScan® and also measurement of liver function tests before and after the intervention. Results There was a non-significant trend toward more severe liver involvement in placebo group comparing to the silymarin group after intervention based on ultrasonography (p = 0.083). Besides, in silymarin group, hepatic involvement grade based on ultrasonography considerably reduced after intervention (p = 0.012). However, no difference was found between two groups based on FibroScan and liver function tests. Conclusion Oral administration of silymarin could significantly reduce hepatotoxicity severity after 1 month of treatment in non-metastatic breast cancer patients treated with AC-T regimen.