Systems, apparatuses, and methods, and for seamlessly protecting memory regions to protect against hardware-based attacks are disclosed. In one embodiment, an apparatus includes a decoder, control logic, and cryptographic logic. The decoder is to decode a transaction between a processor and memory-mapped input/output space. The control logic is to redirect the transaction from the memory-mapped input/output space to a system memory. The cryptographic logic is to operate on data for the transaction.