Lignosulfonate (LS), one of the byproducts of the paper and pulp industry, was mainly used as an energy source in the last decade until the valorization of lignin through different functionalization methods grew in importance. Polymerization using multicopper oxidase laccase (from the Myceliophthora thermophila fungus) is one of such methods, which not only enhances properties such as hydrophobicity, flame retardancy, and bonding properties but can also be used for food and possesses pharmaceutical-like antimicrobial properties and aesthetic features of materials. Appropriate downstream processing methods are needed to produce solids that allow the preservation of particle morphology, a vital factor for the valorization process. In this work, an optimization of the enzymatic polymerization via spray-drying of LS was investigated. The response surface methodology was used to optimize the drying process, reduce the polymerization time, and maximize the dried mass yield. Particles formed showed a concave morphology and enhanced solubility while the temperature sensitivity of spray-drying protected the phenol functionalities beneficial for polymerization. Using the optimized parameters, a yield of 65% in a polymerization time of only 13 min was obtained. The experimental values were found to be in agreement with the predicted values of the factors (R2: 95.2% and p-value: 0.0001), indicating the suitability of the model in predicting polymerization time and yield of the spray-drying process.