Transformation of naphthopyran into a colored merocyanine species in polymeric materials is achieved using mechanical force. We demonstrate that the mechanochemical reactivity of naphthopyran is critically dependent on the regiochemistry, with only one particular substitution pattern leading to successful mechanochemical activation. Two alternative regioisomers with different polymer attachment points are demonstrated to be mechanochemically inactive. This trend in reactivity is accurately predicted by DFT calculations, reinforcing predictive capabilities in mechanochemical systems. We rationalize the reactivity differences between naphthopyran regioisomers in terms of the alignment of the target C-O pyran bond with the direction of the applied mechanical force and its effect on mechanochemical transduction along the reaction coordinate.