In this work, a Design of Experiments (DoE) approach was adopted to systematically delve into lignin ultrasonication, so as to establish qualitative and quantitative cause-effect relationships between the operating variables (i.e., lignin concentration (C), processing time (t), and ultrasonication power (P)) and the properties of the so-obtained nanoparticles. Aqueous suspensions at different lignin concentrations were subjected to ultrasonic irradiation at different durations and intensities – according to a Box-Behnken design with three factors and three levels. The resulting LNPs were recovered after freeze-drying. The modifications occurring to lignin upon ultrasonic treatment were quantified through dynamic light scattering, transmission electron microscopy, phosphorus-31 nuclear magnetic resonance, differential scanning calorimetry, and gel permeation chromatography, aiding in identifying the factors with the most significant effect on the considered responses (i.e., average particle size (daverage), average particle circularity (CI), content of hydroxyl/carboxyl groups (OH/COOH), and suspended-lignin fraction (xlig,sus)). Interestingly, solely and exclusively nanospheres with perfectly circular profiles were observed to form when certain conditions (i.e., P = 450 W, C = 3 % (w/w)) were simultaneously applied. Furthermore, highly-predictive fitted models were generated to accurately and reliably estimate the responses at any experimental point within the investigation range, and validated by performing simulations. Then, poly(vinyl alcohol)-based blends incorporating 5 % (w/w), 10 % (w/w), and 20 % (w/w) of either pristine or ultrasound-treated lignin were prepared via solvent casting, and characterized through Fourier transform infrared spectroscopy, scanning electron microscopy, differential scanning calorimetry, thermogravimetric analysis, and uniaxial tensile testing. The nanometric size, spherical morphology, and lower molecular weight exhibited by LNPs fostered a stronger matrix-filler interaction and a higher dispersion level of (nano)lignin within PVA, ultimately leading to better-performing (nano)composite materials. This work provides new insights into lignin ultrasonication, demonstrating the possibility of tailoring the properties of the so-obtained nanoparticles by suitably tuning the process parameters.