Obtaining precise solar radiation data is the first stage in determining the availability of solar energy. It is also regarded as one of the major inputs for a variety of solar applications. Due to the scarcity of solar radiation measurement data for many locations throughout the world, many solar radiation models are utilized to predict global solar radiation. Indeed, the most widely used AI technique is artificial neural networks (ANNs). Hitherto, while ANNs have been utilized in various studies to estimate global solar radiation (GSR), limited attention has been given to the architecture of ANN. Thus, this study aimed to: first, optimize the design of one of the faster and most used machine-learning (ML) algorithms, the ANN, to forecast GSR more accurately while saving computation power; second, optimize the number of neurons in the hidden layer to obtain the most significant ANN model for accurate GSR estimation, since it is still lacking; in addition to investigating the impact of varying the number of neurons in the hidden layer on the proficiency of the ANN-based model to predict GSR with high accuracy; and, finally, conduct a comparative study between the ANN and empirical techniques for estimating GSR. The results showed that the best ANN model and the empirical model provided an excellent estimation for the GSR, with a Coefficient of Determination R2 greater than 0.98%. Additionally, ANN architectures with a smaller number of neurons in the single hidden layer (1–3 neurons) provided the best performance, with R2 > 0.98%. Furthermore, the performance of the developed ANN models remained approximately stable and excellent when the number of hidden layer’s neurons was less than ten neurons (R2 > 0.97%), as their performance was very close to each other. However, the ANN models experienced performance instability when the number of hidden layer’s neurons exceeded nine neurons. Furthermore, the performance comparison between the best ANN-based model and the empirical one revealed that both models performed well (R2 > 0.98%). Moreover, while the relative error for the best ANN model slightly exceeded the range, ±10% in November and December, it remained within the range for the empirical model even in the winter months. Additionally, the obtained results of the best ANN model in this work were compared with the recent related work. While it had a good RMSE value of 0.8361 MJ/m2 day−1 within the ranges of previous work, its correlation coefficient (r) was the best one. Therefore, the developed models in this study can be utilized for accurate GSR forecasting. The accurate and efficient estimation of global solar radiation using both models can be valuable in designing and performance evaluation for different solar applications.