Technologies for cryptographic separation of MMIO operations with an accelerator device include a computing device having a processor and an accelerator. The processor establishes a trusted execution environment. The accelerator determines, based on a target memory address, a first memory address range associated with the memory-mapped I/O transaction, generates a second authentication tag using a first cryptographic key from a set of cryptographic keys, wherein the first key is uniquely associated with the first memory address range. An accelerator validator determines whether the first authentication tag matches the second authentication tag, and a memory mapper commits the memory-mapped I/O transaction in response to a determination that the first authentication tag matches the second authentication tag. Other embodiments are described and claimed.