Reactive dyeing of cotton in supercritical carbon dioxide is a green alternative to reduce water consumption and wastewater. Cotton could be successfully dyed and the reaction kinetics was determined; however, several issues need to be clarified for further optimization of the dyeing process. For instance, it was observed that the difluorotriazine dye reacted very fast with cotton but its kinetics showed a negative activation energy. Furthermore, it seemed that fixation was strongly related to the nature of cosolvents methanol and dimethyl sulfoxide. Finally, the dihalogenotriazine dye reacted selectively with cotton in the presence of methanol, commonly used as a model for cotton. A molecular modeling approach was applied to provide explanations for the above-mentioned experimental phenomena. In combination with experimental data, molecular modeling was shown to be a powerful tool for the understanding and optimization of the process of cotton dyeing in supercritical carbon dioxide.