Ghana faces chronic energy insecurity, with 35% of national greenhouse gas (GHG) emissions originating mainly from thermal power sources. This study employs Climate, Land, Energy, and Water systems (CLEWs) modelling to evaluate three energy transition pathways through 2055: Baseline (BAU), Emission Reduction (EMR), and Nuclear Energy Addition (NUC). Results reveal that nuclear energy provides the most cost-effective decarbonization pathway at $51.49 billion, achieving substantial emission reductions by reducing reliance on biofuel and natural gas baseload generation. Conversely, the renewable-heavy EMR scenario, targeting 20.4% natural gas and biofuel emission reduction by 2030, a contribution to the overall 64 Mt CO2eq of Ghana’s emission, costs $97.95 billion, approximately 90% more than the nuclear pathway, due to extensive solar infrastructure, storage, and grid requirements. Both decarbonization scenarios decrease biofuel generation, with EMR achieving a 100 % reduction and NUC reducing biofuel generation by 12.6 %. The model's findings challenge conventional assumptions about the cost- and emission-effectiveness of renewable energy and suggest that nuclear power warrants serious consideration in Ghana's sustainable energy strategy, contingent on timely regulatory framework development and international partnerships.