Serial communication buses are used in electronic systems to interconnect sensors and other devices, but two of the most widely used protocols, I²C and SPI, are vulnerable to bus-wide failures 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. Generalized reusable circuit blocks were designed and integrated into three spacecraft systems for the successful NASA V-R3x mission deployed in January 2021. The addition of serial bus isolation significantly improved system reliability for the V-R3x mission by eliminating single-point failure modes of the I²C and SPI buses interconnecting sensors and radios necessary for mission success. The developed protection schemes are a new tool for decoupling system reliability from serial bus device count and can readily be integrated into existing aerospace systems.