This paper presents performance prediction and optimization of an organic Rankine cycle (ORC) for diesel engine waste heat recovery based on artificial neural network (ANN). An ANN based prediction model of the ORC system is established with consideration of mean squared error and correlation coefficient. A test bench of combined diesel engine and ORC waste heat recovery system is developed, and the experimental data used to train and test the proposed ANN model are collected. A genetic algorithm (GA) is also considered in this study to increase prediction accuracy, and the ANN model is evaluated with different learning rates, train functions and parameter settings. A prediction accuracy comparison of the ANN model with and without using GA is presented. The effects of seven key operating parameters on the power output of the ORC system are investigated. Finally, a performance prediction and parametric optimization for the ORC system are conducted based on the proposed ANN model. The results show that prediction error of the ANN model with using the GA is lower than that without using GA. Therefore, it is recommended to optimize the weights of the ANN model with GA for a high prediction accuracy. The proposed ANN model shows a strong learning ability and good generalization performance. Compared to the experimental data, the maximum relative error is less than 5%. The experimental results after optimizing the operating parameters are very close to ANN's predictions, indicating one or more operating parameters can be adjusted to obtain a higher power output during the experiment process.