Long-lasting, high-resolution neural interfaces that are ultrathin and flexible are essential for precise brain mapping and high-performance neuroprosthetic systems. Scaling to sample thousands of sites across large brain regions requires integrating powered electronics to multiplex many electrodes to a few external wires. However, existing multiplexed electrode arrays rely on encapsulation strategies that have limited implant lifetimes. Here, we developed a flexible, multiplexed electrode array, called “Neural Matrix,” that provides stable in vivo neural recordings in rodents and nonhuman primates. Neural Matrix lasts over a year and samples a centimeter-scale brain region using over a thousand channels. The long-lasting encapsulation (projected to last at least 6 years), scalable device design, and iterative in vivo optimization described here are essential components to overcoming current hurdles facing next-generation neural technologies.