Design and syntheses of aggregation-induced emission (AIE) luminescent materials have attracted persistent attention in recent years. Among the various strategies to design novel AIE-active materials, conversion from aggregation-caused quenching (ACQ) to AIE is one of the most efficient because ACQ molecules are capable of being fluorescent in solution already, just not in the aggregated state. In this study, ACQ-to-AIE conversion was realized by regioisomerization of two rofecoxib derivatives named p-PDRF and o-PDRF. For these two compounds, p-PDRF with a piperidine group located on the para-position exhibited typical ACQ behavior while o-PDRF showed characteristic AIE activity when the piperidine group was relocated to the ortho-position. The single-crystal X-ray analysis revealed that the opposite fluorescent behavior in different states was mainly due to different structural conformations and different modes of molecular packing due to regioisomerization. Furthermore, o-PDRF also displayed apparent solvatochromism, mechanochromism, and acidochromism with reversible multi-stimulus behavior. Powder X-ray diffraction analysis indicated that the planarization of twisted structure and the destroy of crystalline structure was responsible for the tuned solid-state fluorescence. Taken together, the data showed that subtle migration of a piperidine group based on the rofecoxib scaffold altered the fluorescent properties of the two compounds significantly and that compound o-PDRF has the potential to be developed as mechanical-force sensors and pH detectors.