This work aimed to investigate the co-grinding effects of β-cyclodextrin (β-CD) and cucurbituril (CB) on crystalline zaltoprofen (ZPF) in tablet formulation. Crystalline ZPF was prepared through anti-solvent recrystallization and fully analyzed through single-crystal X-ray diffraction. Co-ground dispersions and mono-ground ZPF were prepared using a ball grinding process. Results revealed that mono-ground ZPF slightly affected the solid state, solubility, and dissolution of crystalline ZPF. Co-ground dispersions exhibited completely amorphous states and elicited a significant reinforcing effect on drug solubility. UV-vis spectroscopy, XRPD, FT-IR, DSC, ssNMR, and molecular docking demonstrated the interactions in the amorphous product. Hardness tests on blank tablets with different β-CD and CB contents suggested the addition of β-CD or CB could enhance the compressibility of the powder mixture. Disintegration tests showed that CB could efficiently shorten the disintegrating time. Dissolution tests indicated that β-CD and CB could accelerate the drug dissolution rate via different mechanisms. Specifically, CB could accelerate the dissolution rate by improving disintegration and β-CD showed a distinct advantage in solubility enhancement. Based on the comparative study on β-CD and CB for tablet formulation combined with co-grinding, we found that CB could be considered a promising drug delivery, which acted as a disintegrant.