The present research work investigates the impact of natural and anthropogenic inputs on the chemistry and quality of the groundwater in the Beenaganj-Chachura block of Madhya Pradesh, India. A total of 50 groundwater samples were examined for Nitrates, Fluoride, chlorides, TDS, Calcium, Magnesium, pH, total hardness and conductivity and their impact on Entropy Weighted Water Quality Index (EWQI) and Pollution Index of Groundwater (PIG) was investigated via the Response Surface Methodology (RSM) using the Central Composite Design (CCD). According to analytical findings, Calcium (Ca), Magnesium (Mg), Chloride ions (Cl−), Sulphate ions (SO42−), and Nitrate ions (NO3−) exceed the Desired Limit (DL) and permitted limit (PL) set by the Bureau of Indian Standards (BIS) and the World Health Organization (WHO). According to PIG findings, 76%, 16%, and 8% of groundwater samples, respectively, fell into the insignificant, low, and moderate pollution categories. The regression coefficients of the quadratic RSM models for the experimental data provided excellent results. Thus, RSM provides an excellent means to obtain the optimized values of input parameters to minimize the PIG values.