The first total synthesis of gastrodinol, an unprecedented poly-p-cresol-substituted natural product with a rearranged and reconstructed C ring moiety, is reported. Our synthesis features a convergent fragment approach. The Sonogashira coupling reaction forges the two segments together to furnish the conjugated ene-yne. Photocatalytic 6π electrocyclization followed by spontaneous aromatization is used to construct the tetrasubstituted B ring at the late stage. Further study shows that gastrodinol exhibits significant cytotoxic activity against five human cancer cell lines in vitro (IC50 2.5-3.8 μM).