Based on our previous work and calculational chemistry, the pore-size distribution is the key factor which influences glabridin uptakes on resins. In addition, micropores and mesopores in the range of 1.8–5.4 nm are proper for glabridin adsorption. Based on this, a series of novel microporous and mesoporous self-crosslinked polystyrene resins (named as XT2) were synthesized by Friedel–Crafts reaction after different reaction time and utilized to adsorb glabridin in aqueous solution. The adsorption behaviors of the synthetic resins were studied systematically in terms of adsorption capacity, equilibrium time, isotherm adsorption and regeneration properties and compared with a commercial adsorbent (BMKB-1) which was screened out as the optimal macroporous adsorption resin (MAR) for glabridin based on our previous work. The characteristic methods of BET surface area, pore size distribution, Fourier transform infrared spectroscopy and scanning electron microscopy were investigated to analyze the resins and adsorption process. The glabridin uptakes on XT2-10 were remarkably larger than those of macroporous adsorption resin BMKB-1. The maximum adsorption capacity of XT2-10 is up to 43.69 mg/g for glabridin. The adsorption isotherms could be well described by the Freundlich model, and the adsorption kinetics were fitted by both pseudo-second-order kinetic equation and intra-particle diffusion model. The adsorption mechanism was a synergistic effect of specific surface area, molecular sieving effect, and multiple adsorption interactions including hydrogen bonding and π–π stacking. The glabridin uptakes decreased to approximately 93.23% after five cycles of adsorption–desorption, exhibiting an excellent reusability and remarkable regeneration. Based on these results, this research not only opens up the possibility of synthesizing microporous and mesoporous self-crosslinked polystyrene resins, but also provides guidance for understanding the adsorption mechanism of purification of flavones from herbal plants.