The development of synthetic strategies enabling the stereo- A nd regio-selective synthesis of organic molecules is indispensable in the pharmaceutical industry. This work describes a stereo- A nd regioselective synthesis of (E)/(Z)-1,1-disubstituted-3-(1-arylalkylidene)-1,3-dihydroisobenzofurans catalyzed by palladium. The DHIBFs are achieved from readily available aryl bromides and ortho-alkyne tertiary alcohols via intermolecular aryl Heck coupling and intramolecular oxo-cyclization of the suitably situated hydroxyl group. Significantly, it was demonstrated that a Z-isomer was formed as a substantial isomer at 80 °C for 6 h, whereas the stable E-isomer was the predominant one at slightly vigorous conditions (100 °C for 12 h). In addition, careful observation has also led to the realization that this double isomerization from Z-to E-isomer was triggered in the NMR tube itself in CDCl3 at room temperature. Significantly, this protocol, for the first time, enabled the synthesis of heavily substituted dihydroisobenzofurans, especially, bearing a tetra-substituted double bond. © 2021 American Chemical Society.