Although there are many studies related to design, modeling, and optimization of fused deposition modeling (FDM) process parameters in the literature, the absence of a systematic approach to increase the reliability of model selection and optimization results is an important shortcoming that must be addressed. To make up for this deficiency, a new strategy was proposed to obtain desired quality on mechanical properties by adjusting FDM process parameters. This attempt involves manufacturing, modeling, and optimization point of view. The D-optimal method was employed to form experiment set, including process parameters. A hybrid approach neuro regression combining artificial neural network (ANN) and regression analysis together was used for modeling of FDM process. The most significant advantage of the neuro-regression approach compared to ANN is that the mathematical models can be used directly without needing any transformation. This is not possible in neural networks and, therefore, significantly limits and complicates the use of models obtained using ANN. The present study aims at optimization of the FDM process parameters, including infill density, infill pattern, layer thickness, and print speed on ultimate strength, fracture strength, and fracture strain for polylactide (PLA). In this regard, modified versions of the optimization algorithms Differential Evolution, Nelder Mead, and Simulated Annealing were used to find the best or elite designs. Linear or nonlinear models consisting of polynomial, trigonometric, and logarithmic expressions and their hybrid forms were employed to define the strength and strain behavior of PLA. It is concluded that (a) implementations of the optimization algorithms provide a 19% improving the minimum strain value if it is compared with the experimental results, (b) infill pattern types ( x2) were found as honeycomb, triangle, and cubic for the designs in terms of maximum fracture strength, minimum strain, and maximum ultimate tensile strength respectively, (c) many alternatives near optimum local designs could be obtained based on Nelder Mead algorithm for fracture strength and ultimate strength parameters. Thus, this allows work in a wide range of applications without depending on a single result for production.