Silicon dioxide (SiO2), a new type of inorganic nonmetallic material, has been widely used in people's livelihood and military industry. For silicon dioxide-based applications, ultra-precision micromachining is a crucial component that impacts the performance of the finished products. This research reports the precise micromachining of silicon dioxide wafers by femtosecond laser. A prediction model for groove processing size is developed, and an experiment is carried out to investigate the silicon dioxide groove processing technology. The effects of processing parameters that include laser power, scanning speed, scanning repetitions, and defocus amount on the processed properties of grooves, the heat affected zone, and processed roughness are discussed. The variable defocus processing method is proposed, which can effectively improve the inclination angle of the groove wall and the quality of the machined groove. Moreover, scanning electron microscopy is used to analyze the groove morphology, allowing for the improvement of surface quality and processing parameter optimization.