A large power generation facility is a complex multi-criteria system associated with multivariate couplings, high dependency, and non-linearity among the operating variables which present a major challenge to ensure efficient power production. In this research, an integrated artificial intelligence (AI) and response surface methodology (AI-RSM) framework to achieve the efficient power production operation of a 660 MW coal power plant is presented. Two AI algorithms, i.e., extreme learning machine (ELM) and support vector machine (SVM) are trained comprehensively on the power plant's operational data and are validated as well. Full factorial design of experiments on the three levels of the operating parameters are constructed and simulated from the better performing AI model which is an effective non-linear representation of the complex power plant operation. RSM analysis is carried out under three power generation scenarios to simulate the effective values of the operating variables which are tested on the power plant's operation and a reasonable agreement is found with the experimental observations. The notable improvement in fuel consumption rate, thermal efficiency, and heat rate of the power plant under Half Load, Mid Load, and Full Load capacity of the power plant is achieved by the AI-RSM framework enabled analyses. It is estimated that annual reduction in CO2, CH4 and Hg emissions measuring 210 kg tons per year (kt/y), 23.8 t/y and 2.7 kg/y, respectively can be obtained corresponding to Mid Load operating state of the power plant. The research presents the reliable and robust utilization of AI-RSM framework for simulating the effective operating conditions for the fossil-based power plants’ operation with an eventual goal to improve the techno-environmental performance which is expected to contribute to net-zero emissions goal from the energy sector.