The present disclosure is directed to systems and methods for mitigating or eliminating the effectiveness of a side-channel based attack, such as one or more classes of an attack commonly known as Spectre. Novel instruction prefixes, and in certain embodiments one or more corresponding instruction prefix parameters, may be provided to enforce a serialized order of execution for particular instructions without serializing an entire instruction flow, thereby improving performance and mitigation reliability over existing solutions. In addition, improved mitigation of such attacks is provided by randomizing both the execution branch history as well as the source address of each vulnerable indirect branch, thereby eliminating the conditions required for such attacks.