Achieving long-term climate mitigation goals in Japan faces several challenges, starting with the uncertain nuclear power policy after the 2011 earthquake, the uncertain availability and progress of energy technologies, as well as energy security concerns in light of a high dependency on fuel imports. The combined weight of these challenges needs to be clarified in terms of the energy system and macroeconomic impacts. We applied a general equilibrium energy economic model to assess these impacts on an 80% emission reduction target by 2050 considering several alternative scenarios for nuclear power deployment, technology availability, end use energy efficiency, and the price of fossil fuels. We found that achieving the mitigation target was feasible for all scenarios, with considerable reductions in total energy consumption (39%–50%), higher shares of low-carbon sources (43%–72% compared to 15%), and larger shares of electricity in the final energy supply (51%–58% compared to 42%). The economic impacts of limiting nuclear power by 2050 (3.5% GDP loss) were small compared to the lack of carbon capture and storage (CCS) (6.4% GDP loss). Mitigation scenarios led to an improvement in energy security indicators (trade dependency and diversity of primary energy sources) even in the absence of nuclear power. Moreover, preliminary analysis indicates that expanding the range of renewable energy resources can lower the macroeconomic impacts of the long term target considerably, and thus further in depth analysis is needed on this aspect.