Background: The sorghum stem can be divided into the pith and rind parts with obvious differences in cell type and chemical composition, thus arising the different recalcitrance to enzyme hydrolysis and demand for different pretreatment conditions. The introduction of organic solvents in the pretreatment can reduce over-degradation of cellulose and hemicellulose, but significance of organic solvent addition in pretreatment of different parts of sorghum stem is still unclear. Valorization of each component is critical for economy of sorghum biorefinery. Therefore, in this study, NaOH-ethanol pretreatment condition for different parts of the sorghum stem was optimized to maximize p-coumaric acid release and total reducing sugar recovery. Result: Ethanol addition improved p-coumaric acid release and delignification efficiency, but significantly reduced hemicellulose deconstruction in NaOH-ethanol pretreatment. Optimization using the response surface methodology revealed that the pith, rind and whole stem require different NaOH-ethanol pretreatment conditions for maximal p-coumaric acid release and xylan preservation. By respective optimal NaOH-ethanol pretreatment, the p-coumaric acid release yields reached 94.07%, 97.24% and 95.05% from pith, rind and whole stem, which increased by 8.16%, 8.38% and 8.39% compared to those of NaOH-pretreated samples. The xylan recoveries of pith, rind and whole stem reached 76.80%, 88.46% and 85.01%, respectively, which increased by 47.75%, 15.11% and 35.97% compared to NaOH pretreatment. Adding xylanase significantly enhanced the enzymatic saccharification of pretreated residues. The total reducing sugar yields after respective optimal NaOH-ethanol pretreatment and enzymatic hydrolysis reached 84.06%, 82.29% and 84.09% for pith, rind and whole stem, respectively, which increased by 29.56%, 23.67% and 25.56% compared to those of NaOH-pretreated samples. Considering the separation cost of the different stem parts, whole sorghum stem can be directly used as feedstock in industrial biorefinery. Conclusion: These results indicated that NaOH-ethanol is effective for the efficient fractionation and pretreatment of sorghum biomass. This work will help to understand the differences of different parts of sorghum stem under NaOH-ethanol pretreatment, thereby improving the full-component utilization of sorghum stem.