This study was conducted in order to assess the chemistry (41 metalloids and heavy metals and 16 physico-chemical indicators) of groundwater sampled from the protected area of the Tisa River Basin during the months of 2021. Pollution indices were used in order to determine the potential metal pollution level. Consequently, a non-carcinogenic risk assessment of metal through the ingestion of water was done. The results indicated general contamination with ammonium, chloride, iron, and manganese. The samples were rich in Cu, Mg, and Pb, but lower than the maximum limits. Significant correlations were noticed between Al-Fe, Mn-Fe, Mn-Ni, and Cr-Zn, as well as the metal content and pollution index scores. The metal pollution indices indicated three pollution levels (low, medium, and high) based on the metal content and standards regarding the water quality used for drinking purposes. The pollution indices scores ranged from 1.52–41.2. A human health risk assessment indicated no potential non-carcinogenic risk for the studied metals through the consumption of groundwater. The results of three different tools (chronic daily intake, hazard quotient, and hazard index) were below the critical value, except for the aluminium in two samples. This study is one of the first attempts to evaluate the quality of groundwater sources associated with the human health risks of the studied metals from the Tisa River Basin protected area. Based on this research, strategies for managing and controlling the risks can be developed.