The problem of the anisotropy and heterogeneity of karstic aquifers has been previously described. The Opole–Zawadzkie Major Groundwater Body (south-west Poland) was chosen for this investigation. The parameters for anisotropy were analysed on the basis of well yield and observation of macro-fractures (field scale) compared with micro-fractures. Statistical tools were used to assess the directions and values of anisotropy. The estimated parameters were tested on two different models realized in Visual Modflow code. The anisotropy of hydraulic conductivity was recognized as an essential factor for groundwater flow direction and water table depletion prognosis as well as for water budget modification. The second model (M2), representing anisotropy flow conditions, gave an 11% lower value of safe yield in comparison with the first model (M1-isotropic). Additionally, anisotropy conditions caused water table lowering and limitation of aquifer recharge. The results of these studies indicate the need for more attention to be paid to the anisotropy problem in the area, where fracture-karstic aquifers are the main source of groundwater supply.