Luminescent molecules with aggregation-induced emission (AIE) property or AIE-active luminogens (AIE-gens) are typical stimuli-responsive materials. Many AIE-gens have shown luminescent responses to mechano-, thermo-, electro-, vapo-, and/or solvato-stimulus, but the detailed structure-property relationship has been addressed for only a few of them. Here, we report a tetraphenylethene (TPE) derivative with pyridyl modifiers and ethynylene bridges. The (Z)- and (E)-isomers are clearly purified, and both of them are AIE-active and demonstrate multiple luminescent responses to external stimuli. Distinct from other reported TPE derivatives, the two isomers show negative solvatochromism due to the large dipole in the ground electronic state. By correlating with the single crystal structures, the subtle differences in quantum efficiency and emission peak wavelength of the solids of the (Z)- and (E)-isomers are rationally explained. Moreover, the ground powder of the (E)-isomer can recover its emission color from green to blue in the air at room temperature but the (Z)-isomer cannot. This difference is interpreted by a mechanism of water-triggered conformational variation, which depends on the hydrogen bond formation between pyridyl moieties and water molecules in the air. In addition to the reversible emission color changes by cyclic grinding-fuming treatments, both of the isomers exhibit a reversible luminescent response to acid-base treatments by switching the emission color between green (basic) and yellow (acid), owing to the incorporation of pyridyl units into the molecule. The unprecedented multiple stimuli-responsive behaviors and clear mechanism explanations allow this kind of AIE-gens to be promising smart materials.