Serial communication buses are used in electronic systems to interconnect sensors and other devices, but two of the most widely used protocols, i.e., interintegrated circuit (I2C) and serial peripheral interface (SPI), are vulnerable to bus-wide failure if even one device on the bus malfunctions. For aerospace applications demanding increasingly more distributed processing and sensing capability, the compounding risk to system reliability as device count scales becomes a limiting factor in mission scope, performance, and lifetime. We propose a simple external circuit to be added to each node on a communication bus that automatically isolates the node in the event of device failure. By automatically isolating failed devices, the integrity of the bus is preserved without requiring additional signals or processing overhead from the host controller. In this article, I2C and SPI isolation circuits are simulated, fabricated, and experimentally verified to be effective at preserving bus integrity in the event of peripheral device failure. The isolation circuits were integrated into three spacecraft for the successful NASA V-R3x mission and found to significantly improve system reliability by eliminating single-point failure modes of the I2C and SPI buses. The developed protection schemes are a valuable tool for decoupling system reliability from serial bus device count and can readily be integrated into the existing aerospace systems.