Two of the key questions to be addressed are whether and how one can turn cocoon silk into fascinating materials with different electronic and optical functions so as to fabricate the flexible devices. In this review, a comprehensive overview of the unique strategy of mesoscopic functionalization starting from silk fibroin (SF) materials to the fabrication of various meso flexible SF devices is presented. Notably, SF materials with novel and enhanced properties can be achieved by mesoscopically reconstructing the hierarchical structures of SF materials. This is based on rerouting the refolding process of SF molecules by meso‐nucleation templating. As‐acquired functionalized SF materials can be applied to fabricate bio‐compatible/degradable flexible/implantable meso‐optical/electronic devices of various types. Consequently, functionalized SF can be fabricated into optical elements, that is, nonlinear photonic and fluorescent components, and make it possible to construct silk meso‐electronics with high‐performance. These advances enable the applications of SF‐material based devices in the areas of physical and biochemical sensing, meso‐memristors, transistors, brain electrodes, and energy generation/storage, applicable to on‐skin long‐term monitoring of human physiological conditions, and in‐body sensing, information processing, and storage. Owing to the mesoscopic multi‐levels of structures and the intermolecular nucleation control mechanism, a revolutionary materials strategy from mesoscopic reconstruction to the fabrication of new conceptual meso‐electronic/photonic devices based on silk fibroin materials is presented. This development turns out to be very crucial in the field of flexible electronics, optics/photonics, and biomedical/healthcare, which leads to a New Silk Road in big health and the artificial intelligence era.