Groundwater is essential for maintaining ecosystem health and overall well-being as a pivotal resource for plants and animals. The increasing public consciousness of the deterioration of groundwater quality has emphasized the significance of undertaking extended evaluations of groundwater water quality, particularly in regions undergoing substantial hydrological alterations. This study primarily aims to investigate the spatio-temporal variations in groundwater quality and evaluate its suitability for potable purposes in the region of Madhya Pradesh. The study combines the Mann-Kendall (MK) test and Sen's Slope (SS) to analyze the changes in groundwater quality of all 51 districts of Madhya Pradesh, India, utilizing 12 water quality indices using MATLAB. Data was sourced from the Central Ground Water Board (CGWB) in India from the year 2001–2021. The data was then tested for homogeneity at all 1154 sampling stations using the software XLSTAT. Piper plot clustering characterized the state's groundwater as bicarbonate-calcium-magnesium (HCO3−-Ca2+-Mg2+) type. The study found that the groundwater in the area is heavily impacted by high levels of nitrate and hardness, which is caused by an increase in multivalent cations. The water was classified as ranging from hard to extremely hard, and approximately 25.49% of the state's groundwater has nitrate levels that exceed the acceptable limits. The MK test showed a significant increasing correlation in trends for parameters such as nitrate, sulfate, fluoride, chloride, bicarbonate, total hardness, and electrical conductivity. It also showed a significant decreasing correlation for calcium, magnesium, potassium, and sodium. These results were observed at a confidence level of 95%. The analysis of trends has shown that human-related factors have a considerable effect on the characteristics of groundwater quality. It is therefore recommended that such human-related factors be taken into consideration when developing policies for managing groundwater resources. Consequently, these policies should emphasize the strict enforcement of rules and standards that limit the overuse of fertilizers, ensure the appropriate disposal of municipal solid and liquid wastes, and regulate industrial pollutants.