Bioimplants that incorporate active electronic components at the tissue interface rely critically on materials that are biocompatible, impermeable to biofluids, and capable of intimate electrical coupling for high‐quality, chronically stable operation in vivo. This study reports a materials strategy that combines silicon nanomembranes, thermally grown layers of SiO2 and ultrathin capping structures in materials with high dielectric constants as the basis for flexible and implantable electronics with high performance capabilities in electrophysiological mapping. Accelerated soak tests at elevated temperatures and results of theoretical modeling indicate that appropriately designed capping layers can effectively limit biofluid penetration and dramatically extend the lifetimes of the underlying electronic materials when immersed in simulated biofluids. Demonstration of these approaches with actively multiplexed, amplified systems that incorporate more than 100 transistors in thin, flexible platforms highlights the key capabilities and the favorable scaling properties. These results offer an effective encapsulation approach for long‐lived bioelectronic systems with broad potential for applications in biomedical research and clinical practice.