Lyocell is treated as a biodegradable, sustainable, and low-carbon emission cellulose fiber, but it possesses a high fibrillation tendency in the dyeing process which is generally conducted at alkaline, wet and high-temperature conditions. The fibrillation phenomenon seriously reduces the product quality and affects its application in eco-textiles. In response to the problem, a greener and simple fibrillation prevention treatment was innovatively conducted before the coloration process to enhance the interaction of Lyocell cellulose macromolecular chains. A nonionic crosslinker with isocyanate reactive groups was applied for the fibrillation control. The mechanism of the reaction between the nonionic crosslinker and Lyocell cellulose chains was determined through the measurements of fiber swelling, dynamic surface tension, Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). It was found that the fibril interaction was significantly enhanced with reduced lateral swelling of Lyocell fibers. The fibrillation tendency was greatly reduced at the treatment condition of 20 g/L, 175 °C, and 80 s. Moreover, the interaction between cellulose chains was further improved after dyed with bifunctional reactive dyes. In comparison to commercial cationic and anionic crosslinkers, the nonionic sample not only showed little effect on the dye fixation, but also added good wrinkle resistance to Lyocell fabrics. The method showed the advantages of a shorter process and low chemical consumption compared to the conventional Lyocell dyeing process. Therefore, this work may promote the development of Lyocell fabric in high-quality and eco-friendly textiles.