Cellulose fibrils are the structural backbone of plants and, if carefully liberated from biomass, a promising building block for a bio-based society. The mechanism of the mechanical release-fibrillation-is not yet understood, which hinders efficient production with the required reliable quality. One promising process for fine fibrillation and total fibrillation of cellulose is cavitation. In this study, we investigate the cavitation treatment of dissolving, enzymatically pretreated, and derivatized (TEMPO oxidized and carboxymethylated) cellulose fiber pulp by hydrodynamic and acoustic (i.e., sonication) cavitation. The derivatized fibers exhibited significant damage from the cavitation treatment, and sonication efficiently fibrillated the fibers into nanocellulose with an elementary fibril thickness. The breakage of cellulose fibers and fibrils depends on the number of cavitation treatment events. In assessing the damage to the fiber, we presume that microstreaming in the vicinity of imploding cavities breaks the fiber into fibrils, most likely by bending. A simple model showed the correlation between the fibrillation of the carboxymethylated cellulose (CMCe) fibers, the sonication power and time, and the relative size of the active zone below the sonication horn.