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Background Aidi Injection (ADI), a Chinese herbal preparation with anti-cancer activity, is used for the treatment of hepatocellular carcinoma (HCC). Several clinical studies have shown that co-administration of ADI with doxorubicin (DOX) is associated with reduced toxicity of chemotherapy, enhanced clinical efficacy and improved quality of life for patients. However, limited information is available about the herb-drug interactions between ADI and DOX. The study aimed to investigate the pharmacokinetic mechanism of herb-drug interactions between ADI and DOX in a rat model of HCC. Methods Experimental HCC was induced in rats by oral administration of diethylnitrosamine. The HCC rats were pretreated with ADI (10 mL/kg, intraperitoneal injection) for 14 consecutive days prior to administration of DOX (7 mg/kg, intravenous injection) to investigate pharmacokinetic interactions. Plasma concentrations of DOX and its major metabolite, doxorubicinol (DOXol), were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Results Preadministration of ADI significantly altered the pharmacokinetics of DOX in HCC rats, leading to increased plasma concentrations of both DOX and DOXol. The area under the plasma drug concentration-time curve (AUCs) of DOX and DOXol in rats pretreated with ADI were 3.79-fold and 2.92-fold higher, respectively, than those in control rats that did not receive ADI. Conclusions Increased levels of DOX and DOXol were found in the plasma of HCC rats pretreated with ADI.