Nineteen elements were analyzed by ICP-MS in surface water from 44 sampling stations from La Plata Basin (South America), including 5 countries and 7 different environments (streams, rivers, meanders, flood valleys, wetland, dam, delta and estuary). A multi-elemental pollution index (EPI) was employed for classifying the water quality while, the potential non-carcinogenic risk through direct ingestion and skin contact were assessed using Hazard Quotients (HQ). Except Fe (2.5–692 μg/L), elements were in accordance to the quality standards for drinking and biota aquatic protection set by international guidelines. EPI indicated a critical scenario for 10 sampling sites (dam, estuary and some meanders, rivers and streams), while the remaining 34 sites were classified within the high pollution status. HQ indicated that water would not be safe (HQ = 1.0–2.11) for human consumption in 5 areas (wetland and rivers and estuary) while, results indicated that there would be no risk (HQ = 0.0005–0.01) through chronic water contact. The main contributors to the HQ indices were As (up to 6.3 μg/L) and Li (up to 49.9 μg/L). Correlations (r ≥ 0.8) such as LiB, LiAs, LiSr, LiBa, LiU, Li-conductivity, BAs, BSr, BBa, BU, B-conductivity, SrBa, SrU, Sr-conductivity provided powerful information about natural sources of some elements. Principal component analysis showed relations between elements and environments such as As, Li, Cs with Andes Mountains and Al and Fe with Atlantic forest. Results allowed to propose management policy recommendations based on strategies for reducing the direct water ingestion, removal methods, and implementation of monitoring programs in the most affected water bodies.