Highly functionalized xanthenes possess an impressive range of bioactivities and daunting synthetic challenge due to their unique ring systems and stereocenters. Here, we report an unprecedented ketyl radicals-induced skeletal rearrangement reaction of spirodihydrobenzofurans, enabled by zero-valent iron as reducing agents via photoredox catalysis, facilitating the facile preparation of various highly functionalized xanthenes. The features of this protocol include high chemo- and regioselectivity, exceptionally mild conditions, a broad substrate scope, scalability to gram-scale quantities, and consistent delivery of good to excellent yields. Mechanistic studies rationalize the function of this zero-valent iron-based reactivity in radical generation. Notably, this reaction was applied to the first asymmetric total synthesis of the complex polycyclic xanthene ent-myrtucomvalones E-F. Moreover, this work led to the discovery of an agent with highly effective antiosteosarcoma activity in vitro and in vivo, potentially paving the way for the development of new xanthene-based candidates for osteosarcoma treatment.