Groundwater is a vital natural resource required to satisfy the domestic and agricultural needs. In general, human health is linked to the quality of the consumed water. For instance, long-term exposure to high nitrate levels in groundwater may cause problems. Hence, the present study was conducted to assess the nitrate contamination of groundwater as well as its related health risks for the inhabitants of the Sfax region, Sahel Tunisia. Irrigation groundwater suitability has been evaluated with sodium content (%Na), electrical conductivity (EC), magnesium hazard (MH), sodium adsorption ratio (SAR), permeability index (PI), Kelly's ratio (KR) and soluble sodium percent (SSP). The results indicate that the selected groundwater is characterized by low to moderate quality for irrigation. Furthermore, the drinking water quality index (DWQI) was assessed using potential of hydrogen (pH), total dissolved solids (TDS), magnesium (Mg2+), calcium (Ca2+), sodium (Na+), chloride (Cl-), sulfate (SO42-), potassium (K+), bicarbonate (HCO3-) and nitrate (NO3-). The results indicate that 3.63% of samples have good quality of water, while 41.82% have poor to very poor water quality and the rest (54.55%) are unfit for drinking. The nitrate pollution index (NPI) model revealed that about 42% of the samples present significant to very significant type of pollution. Based on human health risk assessment, the children are at higher risks compared to the other affected groups. The obtained results could be used as a basic document for realistic management of groundwater quality and to provide an overview for decision-making authorities to take necessary actions.