AIM: To explore the pharmacokinetic interactions between sorafenib and dapagliflozin in rats and to provide some theoretical basis for the rational clinical use of the two drugs. METHODS: An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) method was developed for the simultaneous determination of sorafenib and dapagliflozin. Male SD rats were randomly divided into 5 groups (6 rats in each group), including 100 mg/kg sorafenib group, 0.5 mg/kg dapagliflozin group, 1 mg/kg dapagliflozin group, and 100 mg/kg sorafenib combined with 0.5 mg/kg dapagliflozin group and 100 mg/kg sorafenib combined with 1 mg/kg dapagliflozin group, for sorafenib and dapagliflozin drug interaction study. All samples were analyzed using a validated UPLC/MS/MS method, and the main pharmacokinetic parameters were calculated by compartment model. RESULTS: 1 mg/kg dapagliflozin increased the Cmax, AUC0-t and AUC0-∞ of sorafenib by 52.5%, 38.1% and 37.7%, respectively, and 0.5 mg/kg dapagliflozin increased the AUC0-t and AUC0-∞ of sorafenib by 36.3% and 36.3%. CONCLUSION: Pharmacokinetic interactions may exist between sorafenib and dapagliflozin, active surveillance for treatment and toxicity should be required when the two drugs combined together in clinical practice.