The catalytic valorization of cellulose as feedstock for the large-scale production of liquid fuels and value-added chemicals is currently subject to extensive research. Isosorbide as an important intermediate for the synthesis of a wide range of pharmaceuticals, chemicals and polymers, its efficient production from natural cellulose is very important. Here we report a two-step sequential process where cellulose is firstly depolymerized with Ru/NbOPO4-pH2 catalyst via hydrolysis and hydrogenation and then the resultant sorbitol and sorbitan are directly converted into isosorbide in the presence of solid acid catalyst. The influence of different solid catalysts is investigated in the direct dehydration of sorbitol to isosorbide and finds that NbOPO4-pH2 with the highest acid amount shows the best performance and is used in the sequential process. The reaction conditions (especially reaction temperature and reaction time) are systematically investigated and 56.7% isosorbide yield is obtained under optimal conditions, which is impressive compared with other systems reported with homogeneous or semi-heterogeneous catalysts. This effective catalytic system avoids the use of liquid acid and exhibits excellent cycling stability.