In this study, silk fibroin was extracted from cocoons of silkworms and fabricated into nonwoven mats by electrospinning method. A new model based on the group method of data handling (GMDH) and artificial neural network (ANN) was developed for estimation of the average diameter of electrospun silk fibroin nanofibers. In this regard, concentration, flow rate, voltage, distance, and speed of collector were used as input parameters and average diameter of the fibers was considered as output parameter. Two models were capable to estimate average diameter of fibers with good accuracy. The average absolute relative deviation for GMDH and ANN models was equal to 3.56 and 2.28 %, respectively. Furthermore, due to importance of oxygen delivery to site of injury to promote wound healing, continuity equation for mass transport was employed for prediction of oxygen profile in the system containing wound dressing and skin. The result showed that our prepared wound dressing is capable to pass the oxygen completely to the skin layer and is not acting as a barrier for oxygen delivery to wound site. Since average nanofibers diameter can influence the mat physical, mechanical and biological properties then this model may serve as a useful guide to obtain tailor made and uniform silk nanofibers at various combinations of process variables.