Designing and preparing high-performance lignin-based dispersants are crucial steps in realizing the value-added utilization of lignin on an industrial scale. Such process depends heavily on an understanding of the dispersion mechanism of lignin-based dispersants. Here, atomic force microscopy (AFM) is employed to quantitatively investigate the dispersion mechanism of a lignosulfonate/silica (LS/SiO2) system under different pH conditions. The results show that the repulsive force between SiO2 particles in LS solution is stronger than it is in water, resulting in better dispersion stability. The Derjaguin–Landau–Verwey–Overbeek (DLVO) formula as well as the DLVO formula combined with steric repulsion is utilized for the fitting of the AFM force/distance (F/D) curves between the SiO2 probe and substrate in water and in LS solution. Based on these fitting results, electrostatic and steric repulsive forces are respectively calculated, yielding further evidence that LS provides strong steric repulsion between SiO2 particles. Further studies indicate that the adsorbance of LS on SiO2 (Q), the normalized interaction constant (A), and the characteristic length (L) are the three critical factors affecting steric repulsion in the LS/SiO2 system. Based on the above conclusions, a novel quaternized grafted-sulfonation lignin (QAGSL) dispersant is designed and prepared. The QAGSL dispersant exhibits good dispersing performance for SiO2 and real cement particles. This work provides a fundamental and quantitative understanding of the dispersion mechanism in the LS/inorganic particle system and provides important guidance for the development of high-performance lignin-based dispersants.