The present work is an attempt to model the diameter of Poly Lactic-co-Glycolic Acid (PLGA) nanofibers by utilizing response surface methodology (RSM) and artificial neural networks (ANNs). Hence, determining the optimal electrospinning process conditions to produce a minimum fiber diameter. For modelling the average diameter of nanofibers, RSM approach based on four parameters (polymer concentration, high voltage and needle tip to collector distance and spinning angle) with five-level was compared to ANN technique. In the RSM approach, central composite design (CCD) was used to determine the individual and interaction impacts of the parameters on the average diameter of nanofibers. Several ANNs of single and double hidden layers with different number of cells for each were tried to obtain the best network structure. The experimental and predicted PLGA fiber diameters using an ANN showed a strong correlation, indicating that the network topology of 4-14-1 has good predictability for analyzing factors impacting PLGA fiber diameter. The average absolute relative error for predicting PLGA nanofibers’ diameter using ANN (2.24%) is slightly less than that obtained from RSM (2.59%). The high regression coefficient between the variables and the response (R2 = 0.9636) shows a good second-order polynomial regression model for evaluating experimental data. The R2 value was 0.945, indicating that the ANN model was good fitting with the experimental results. The optimum combinations (PLGA concentration of 26 wt.%, high voltage 22 kV, needle tip to collector distance 20 cm, and spinning angle 60o) were developed by RSM model for electrospinning PLGA nanofiber that can produce fine, consistent, and high-quality nanofibers.