In this study, cellulose nanocrystals (CNC) were chemically extracted from the waste newspapers and acetylated by reacting CNC with acetic anhydride, using sulfuric acid as a catalyst. Response Surface Methodology based on a three-factor factorial design was applied to analyze the interaction effects of reaction temperature, time, and the ratio of nanocellulose and acetic acid (wt/v) on the degree of substitution (DS) which was calculated and compared. Various experimental conditions as reaction temperature (50-70 °C), reaction time (90-150 min), and the ratio of nanocellulose and acetic acid (wt/v) (1:15-1:25) were under investigation. It was found that reaction temperature and its interaction effects have the most significant effects on DS. The acetylated CNC was characterized by FTIR and ¹H-NMR spectroscopy. The highest DS (2.997) was obtained in 90 min and the CNC/acetic acid ratio of 1:15 at 70 °C.