Intercity networks constitute a highly important civil infrastructure in developed countries, as they contribute to the prosperity and development of the connected communities. This was evident after recent strong earthquakes that caused extensive structural damage to key transportation components, such as bridges, overpasses, tunnels and geotechnical works, that in turn led to a significant additional loss associated with the prolonged traffic disruption. In cases of seismic events in developed societies with complex and coupled intercity transportation systems, the interdependency between citizens’ life and road functionality has further amplified the seismically-induced loss. Quantifying therefore, the resilience of road networks, defined as their ability to withstand, adapt to, and rapidly recover after a disruptive event, is a challenging issue of paramount importance towards holistic disaster risk mitigation and management. This study takes into account the above aspects of network resilience to earthquake loading and establishes a comprehensive, multi-criterion framework for mitigating the overall loss expected to be experienced by the community due to future earthquake events. The latter is decoupled into the direct structural damage-related loss and the indirect loss associated with the travel delays of the network users, as well as the wider socio-economic consequences in the affected area. In order to reflect the multi-dimensional nature of loss, a set of novel, time-variant indicators is herein introduced, while cumulative indicators are proposed for assessing the total loss incurred throughout the entire recovery period. This probabilistic risk management framework is implemented into a software to facilitate informed decisions of the stakeholders, both before and after a major earthquake event, thus prioritizing the pre-disruption strengthening schemes and accelerating the inspection and recovery measures, respectively.