The International Maritime Organization aims for net-zero carbon emissions in the maritime industry by 2050. Among various alternatives, route optimization holds an important place as it does not require any additional component-related costs. Especially for wind-assisted ships, the effectiveness of different sailing systems can be improved significantly through route optimization. However, finding the ship’s optimal route is computationally expensive when the totality of possible weather conditions is taken into consideration. To determine the optimal route that minimizes energy consumption, an energy model based on the environmental conditions, ship route and ship speed was built using artificial neural networks. The energy consumed for given input data was calculated using a ship dynamics model and a database was generated to train the artificial neural networks, which predict how much energy is consumed depending on the route followed in given environmental conditions. Then, such networks were exploited to derive the optimal routes for all the relevant operational conditions. It was found that route optimization can reduce the overall ship energy consumption depending on the weather conditions of the environment by up to 9.7% without any increase in voyage time and by up to 35% with a 10% delay in voyage time. The proposed methodology can be applied to any ship by training real weather conditions and provides a framework for reducing energy consumption and greenhouse gas emissions during the service life of ships.