Typical cybersecurity solutions emphasize on achieving defense functionalities. However, execution efficiency and scalability are equally important, especially for real-world deployment. Straightforward mappings of cybersecurity applications onto HPC platforms may significantly underutilize the HPC devices' capacities. On the other hand, the sophisticated implementations are quite difficult: they require both in-depth understandings of cybersecurity domain-specific characteristics and HPC architecture and system model. In our work, we investigate three sub-areas in cybersecurity, including mobile software security, network security, and system security. They have the following performance issues, respectively: 1) The flow- and context-sensitive static analysis for the large and complex Android APKs are incredibly time-consuming. Existing CPU-only frameworks/tools have to set a timeout threshold to cease the program analysis to trade the precision for performance. 2) Network intrusion detection systems (NIDS) use automata processing as its searching core and requires line-speed processing. However, achieving high-speed automata processing is exceptionally difficult in both algorithm and implementation aspects. 3) It is unclear how the cache configurations impact time-driven cache side-channel attacks' performance. This question remains open because it is difficult to conduct comparative measurement to study the impacts. In this dissertation, we demonstrate how application-specific characteristics can be leveraged to optimize implementations on various types of HPC for faster and more scalable cybersecurity executions. For example, we present a new GPU-assisted framework and a collection of optimization strategies for fast Android static data-flow analysis that achieve up to 128X speedups against the plain GPU implementation. For network intrusion detection systems (IDS), we design and implement an algorithm capable of eliminating the state explosion in out-of-order packet situations, which reduces up to 400X of the memory overhead. We also present tools for improving the usability of Micron's Automata Processor. To study the cache configurations' impact on time-driven cache side-channel attacks' performance, we design an approach to conducting comparative measurement. We propose a quantifiable success rate metric to measure the performance of time-driven cache attacks and utilize the GEM5 platform to emulate the configurable cache. / Doctor of Philosophy / Typical cybersecurity solutions emphasize on achieving defense functionalities. However, execution efficiency and scalability are equally important, especially for the real-world deployment. Straightforward mappings of applications onto High-Performance Computing (HPC) platforms may significantly underutilize the HPC devices’ capacities. In this dissertation, we demonstrate how application-specific characteristics can be leveraged to optimize various types of HPC executions for cybersecurity. We investigate several sub-areas, including mobile software security, network security, and system security. For example, we present a new GPU-assisted framework and a collection of optimization strategies for fast Android static data-flow analysis that achieve up to 128X speedups against the unoptimized GPU implementation. For network intrusion detection systems (IDS), we design and implement an algorithm capable of eliminating the state explosion in out-of-order packet situations, which reduces up to 400X of the memory overhead. We also present tools for improving the usability of HPC programming. To study the cache configurations’ impact on time-driven cache side-channel attacks’ performance, we design an approach to conducting comparative measurement. We propose a quantifiable success rate metric to measure the performance of time-driven cache attacks and utilize the GEM5 platform to emulate the configurable cache.