Conventional simulation of fractured carbonate reservoirs is computationally expensive because of the multiscale heterogeneities and fracture–matrix transfer mechanisms that must be taken into account using numerical transfer functions and/or detailed models with a large number of simulation grid cells. The computational requirement increases significantly when multiple simulation runs are required for sensitivity analysis, uncertainty quantification and optimization. This can be prohibitive, especially for giant carbonate reservoirs. Yet, sensitivity analysis, uncertainty quantification and optimization are particularly important to analyse, determine and rank the impact of geological and engineering parameters on the economics and sustainability of different Enhanced Oil Recovery (EOR) techniques. We use experimental design to set up multiple simulations of a high-resolution model of a Jurassic carbonate ramp, which is an analogue for the highly prolific reservoirs of the Arab D Formation in Qatar. We consider CO2 water-alternating-gas (WAG) injection, which is a successful EOR method for carbonate reservoirs. The simulations are employed as a basis for generating datadriven surrogate models using polynomial regression and polynomial chaos expansion. Furthermore, the surrogates are validated by comparing surrogate predictions with results from numerical simulation and estimating goodness-of-fit measures. In the current work, parameter uncertainties affecting WAG modelling in fractured carbonates are evaluated, including fracture network properties, wettability and fault transmissibility. The results enable us to adequately explore the parameter space, and to quantify and rank the interrelated effect of uncertain model parameters on CO2 WAG efficiency. The results highlight the first order impact of the fracture network properties and wettability on hydrocarbon recovery and CO2 utilization during WAG injection. In addition, the surrogate models enable us to calculate quick estimates of probabilistic uncertainty and to rapidly optimize WAG injection, while achieving significant computational speed-up compared with the conventional simulation framework.