Large-scale lifelines, such as high-pressure gas pipelines, often cross seismic-prone areas, and consequently, they are exposed to earthquake-related geohazards (tectonic faulting, landslides and soil liquefaction). Avoiding geologically hazardous areas is not always a techno-economically feasible solution, as the length (i.e., cost) of the infrastructure is increased, whereas crossing such hazardous areas may detrimentally affect the structural performance of the pipeline, necessitating the implementation of costly and sometimes impractical mitigation measures. Therefore, selecting a cost-effective and resilient pipeline route is deemed necessary. The current paper presents an efficient decision-support tool for the optimal route selection of pipelines, which considers -among other criteria- the presence of earthquake-related geohazards. The proposed tool utilizes an enhanced methodology that combines the least-cost path analysis provided by Geographic Information System computational platform with a multi-criteria decision approach. Several routes are derived for various user-defined scenarios, by assigning different weight factors in the adopted design criteria and geohazards. In the present study the decision-support tool is applied in a real case study in northern Greece, where all the aforementioned earthquake-related geohazards coexist, while they may have not been properly assessed during the design of an existing gas pipeline.