The pathway towards decarbonised energy systems involves massive changes in adopted energy vectors, installed technologies, networks roles, and interaction capabilities. To investigate the combination of these effects, this work presents the OMNI-ES modelling framework (Optimisation Model for Network-Integrated Energy Systems), which offers a comprehensive approach to analyse multi-node, multi-vector, multi-sector energy systems. It adopts a detailed temporal and spatial resolution and implements multiple conversion options between energy vectors (electricity, hydrogen, natural gas, biomethane, biofuels, e-fuels, …). The formulation solves the energy vector balances at each time step, taking into account sources, sinks, conversion processes, and storage systems. CO2 flows are also tracked, allowing the introduction of CO2 emission constraints that account for all contributions (fossil and biogenic, direct and indirect) and mitigation measures (capture, re-use, sequestration). In the article, OMNI-ES is applied to investigate an Italian scenario for 2050, adopting a regional (NUTS-2) resolution. The model output yields the cost-optimal energy system configuration that is capable to support the demand with net-zero CO2 emissions. Results show that the need for CO2 balance closure calls in several technologies, including massive renewable power generation (up to 20 times today’s capacities), storage systems (batteries, hydrogen, pumped hydro), biogenic sources (residual biomass and biomethane), and CO2 capture (both on fossil and biogenic sources). Networks emerge as critical elements, as the need to transport energy vectors saturates the expected capacities of grid infrastructures, especially in the case of hydrogen.