Cellulose is the most ancient and abundant polysaccharide on earth. However, the strong hydrogen bond networks and the high crystallinity strongly prevent cellulose from reacting with other compounds to produce higher performance materials. In this work, the investigation via molecular dynamics simulation showed that supercritical 1,1,1,2-tetrafluoroethane (SC R134a) could effectively destroy the strong hydrogen bond networks of cellulose and activate cellulose. Furthermore, experiments were also conducted to support the simulation results, where cellulose was activated via introducing SC R134a and subsequently used in the synthesis of cellulose acetate. The experimental results revealed that SC R134a exhibited a prominent effect on activating cellulose. The crystallinity of cellulose decreased from 0.926 to 0.686 after being activated by SC R134a. In addition the morphology (SEM) of cellulose suggested that the average diameter increased by 25% and numerous cracks appeared on the outer surface of cellulose fibers. Moreover, the consumption of reagents for synthesizing cellulose acetate decreased sharply, especially for acetic acid, which was only 25% of that used in industry, therefore, making the process much more green and energy-saving.