Despite the many existing fibrillation processes for the production of cellulose nanofibrils (CNFs), their exact destructuration effects on fibers remain poorly understood. This work reports the use of disk refining, twin-screw extrusion (TSE), ultra-fine grinding and homogenization for CNF production, alone or in combinations. The same raw material (birch fibers) and pretreatment (enzymatic hydrolysis) were used for comparable process conditions, with a systematic measurement of the energy consumption and a calculation of the process theoretical shear rates. The modifications of cellulose fiber and nanofibril properties were assessed by morphological analysis, optical microscopy, transmission electron microscopy (TEM), X-ray diffraction (XRD), nuclear magnetic resonance (NMR), tensile tests and multi-scale quality index analysis. The water retention value (WRV) and degree of polymerization (DP) were also measured. All processes resulted in 8–14 nm-wide CNFs as well as larger CNF bundles. Residual fiber fragments were observed after refining and TSE. The latter resulted in the most significant decrease of crystallinity index (CI), DP and mechanical properties, while CNFs produced by ultra-fine grinding and homogenization displayed the best mechanical and optical properties. These processes were then combined with a preliminary disk refining step, to assess the influence of the morphology of the initial fibers on their fibrillation efficiency. Such combinations had a negative effect for TSE and homogenization. Lower properties were obtained for these samples, compared to CNFs produced by the processes used individually. In contrast, the combination of disk refining and ultra-fine grinding was found to greatly enhance the resulting CNF properties, with a significant increase in optical transmittance. These results provide an insight on the destructuration effects of each process, and pave the way to further research on the physical phenomena at work.