Shale-gas production has gained worldwide attention over the past several years. Production from shale-gas reservoirs requires horizontal drilling with multiple hydraulic fracturing to obtain the most economical production. However, there are high cost and uncertainty because of many inestimable and uncertain parameters (e.g., reservoir permeability, porosity, fracture spacing, fracture halflength, fracture conductivity, gas desorption, geomechanics, and existing natural fractures). Therefore, the development of a way to quantify uncertainties and optimization of shale-gas production in an efficient and practical method is clearly desirable.In this paper, we present a user-friendly and efficient framework to obtain the optimal gas-production scenario by optimizing the uncertain factors by integrating several commercial simulators, an economic model, design of experiment (DoE), and response-surface methodology (RSM) with a global optimization search engine. Specifically, we use factorial design to screen insignificant factors and find the most influential design and uncertain factors; then, we use RSM to design over those most influential factors to fit a response surface using net present value (NPV) as the objective function; finally, we identify the most economical production scenario under conditions of uncertainty. Eight uncertain parameters [i.e., porosity, permeability, reservoir thickness, reservoir pressure, bottomhole pressure (BHP), fracture spacing, fracture half-length, and fracture conductivity] with a reasonable range on the basis of Barnett-shale information are investigated. Also, different gas prices are considered for the optimization process.This framework is effective and efficient for hydraulic-fracturing-treatment design and production-scheme optimization in unconventional gas reservoirs. It can contribute to providing guidance for engineers to modify the design of a hydraulic-fracture treatment before the actual fracture treatment.