With the diminishing return from Moore’s Law, system-technology co-optimization (STCO) has emerged as a promising approach to sustain the scaling trends in the VLSI industry. By bridging the gap between system requirements and technology innovations, STCO enables customized optimizations for application-driven system architectures. However, existing research lacks sufficient discussion on efficient STCO methodologies, particularly in addressing the information gap across design hierarchies and navigating the expansive cross-layer design space. To address these challenges, this paper presents Orthrus, a dual-loop automated framework that synergizes system-level and technology-level optimizations. At the system level, Orthrus employs a novel mechanism to prioritize the optimization of critical standard cells using system-level statistics. It also guides technology-level optimization via the normal directions of the Pareto frontier efficiently explored by Bayesian optimization. At the technology level, Orthrus leverages system-aware insights to optimize standard cell libraries. It employs a neural network-assisted enhanced differential evolution algorithm to efficiently optimize technology parameters. Experimental results on 7nm technology demonstrate that Orthrus achieves 12.5% delay reduction at iso-power and 61.4% power savings at iso-delay over the baseline approaches, establishing new Pareto frontiers in STCO.