With the increasing level of intelligence of marine engines, there is an increasing demand for the online monitoring of engines, and marine NOx emissions have been of great concern. In this paper, a NOx simulation model is developed based on virtual measurement technology, which can calculate and predict NOx emissions based on the current operating state parameters of low-speed two-stroke diesel engines. First, the calibrated 3D simulation model is used to design the experiments to obtain the simulation experimental samples. Based on the NOx generation mechanism and diesel engine work-related parameters, the relevant factors were selected as alternative input parameters for the NOx emission model. The correlation analysis was then performed on the input parameters using the grey relational analysis correlation method and the Pearson correlation coefficient, and the principal component analysis method was used to reduce the dimensionality of the relevant factors by minimizing the loss of important information in reducing the complexity of the whole model. Then, the structure-related parameters of the backpropagation neural network (BPNN) were adaptively optimized using the group method of data handling (GMDH) to improve the accuracy of the NOx soft measurement model. Finally, the developed GMDH–BP model was validated with data and compared with the error evaluation index of BPNN and BPNN optimized by genetic algorithm (GA), and the developed NOx simulation model demonstrated high prediction accuracy under the same hyperparameter settings. The result provides technical support for the subsequent realization of the real-time online monitoring of NOx emissions from low-speed marine diesel engines without NOx sensors.