In this paper, p-nitrophenyl α-D-mannopyranoside was readily synthesized with D-mannose as starting material by acetylation, Helferich glycosidation and deacetylation. The effect of mole ratio of reactants, temperature, decompression time, reaction time and the amount of catalyst on stereoselectivity and the yield of Helferich glycosidation was investigated through orthogonal experiment. The results show that the highest yield of 72.4% for the optimal α-stereoselectivity of Helferich glycosidation were based on 2.56 mmol of 1,2,3,4,6-Penta-O-acetyl-D-mannopyranose, with the molar ratio of 1,2,3,4,6-Penta-O-acetyl-D-mannopyranose to p-nitrophenol being 1:4, dosage of catalyst SnCl4 being 0.308 mmol, time of decompression and reaction being 80 min and the temperature being 120 ℃.