System-level Dynamic Binary Translation (DBT) provides the capability to boot an Operating System (OS) and execute programs compiled for an Instruction Set Architecture (ISA) different from that of the host machine. Due to their performance-critical nature, system-level DBT frameworks are typically hand-coded and heavily optimized, both for their guest and host architectures. While this results in good performance of the DBT system, engineering costs for supporting a new architecture or extending an existing architecture are high. In this article, we develop a novel, retargetable DBT hypervisor, which includes guest-specific modules generated from high-level guest machine specifications. Our system simplifies retargeting of the DBT, but it also delivers performance levels in excess of existing manually created DBT solutions. We achieve this by combining offline and online optimizations and exploiting the freedom of a Just-in-time (JIT) compiler operating in a bare-metal environment provided by a Virtual Machine (VM) hypervisor. We evaluate our DBT using both targeted micro-benchmarks as well as standard application benchmarks, and we demonstrate its ability to outperform the de facto standard Q EMU DBT system. Our system delivers an average speedup of 2.21× over Q EMU across SPEC CPU2006 integer benchmarks running in a full-system Linux OS environment, compiled for the 64-bit ARMv8-A ISA and hosted on an x86-64 platform. For floating-point applications the speedup is even higher, reaching 6.49× on average. We demonstrate that our system-level DBT system significantly reduces the effort required to support a new ISA while delivering outstanding performance.