The present disclosure provides a use of a nicotinamide composition in preparation of a drug for treating hand-foot skin reaction (HFSR) induced by sorafenib, the composition being consisted of nicotinamide and sorafenib in a dosage ratio of 2:3. The composition provided by the present disclosure can alleviate the HFSR caused by excessive keratinization induced by sorafenib. This protective effect is achieved by inhibiting HB-EGF/SIRT1 pathway. The present disclosure provides a mechanism of sorafenib-induced HFSR, i.e., the excessive activation of the HB-EGF/SIRT1 pathway, thereby providing a theoretical foundation for clinical research of sorafenib-induced HFSR. The present disclosure also provides a drug that can effectively treat sorafenib-induced HFSR, thereby greatly broadening the clinical application of sorafenib. Nicotinamide is highly clinically feasible due to its moderate price, and thus can be prepared in any suitable formulation according to the requirements.