Techniques are described for providing low-overhead cryptographic memory isolation to mitigate attack vulnerabilities in a multi-user virtualized computing environment. Memory read and memory write operations for target data, each operation initiated via an instruction associated with a particular virtual machine (VM), include the generation and/or validation of a message authentication code that is based at least on a VM-specific cryptographic key and a physical memory address of the target data. Such operations may further include transmitting the generated message authentication code via a plurality of ancillary bits incorporated within a data line that includes the target data. In the event of a validation failure, one or more error codes may be generated and provided to distinct trust domain architecture entities based on an operating mode of the associated virtual machine.