Cooperation of essential oil into film formation results in active packaging materials, which can improve the quality and freshness of the foods and extend the shelf life. In the present study, extraction of starch and essential oil was performed. The active films were developed through the solvent casting method. The influence of avocado seed starch and orange peel essential oil was investigated and optimized using response surface methodology and an artificial neural network on the tensile strength, water vapor permeability, and antimicrobial properties of active films. The results showed that both models performed reasonably well, but trained artificial neural networks have more modeling capability rather than the response surface method. The optimum conditions were found to be orange peel oil of 0.57 g and 30% w/w of avocado seed starch with the values of the corresponding responses of 3.94 MPa, g/ms Pa, and 17.273 mm for tensile strength, water vapor permeability, and inhibition zone, respectively. Generally, the orange peel extract had an effective and promising alternative for the commercial production of antimicrobial packaging films.