The Tocantins–Araguaia basin is one of South America’s largest river systems, across three Brazilian states (Maranhão, Tocantins, and Pará), within the Legal Amazon region. Despite draining extensive Cerrado savanna and rainforest ecosystems, it has suffered significant degradation, notably in the past 40 years. Human activities, including agricultural expansion, deforestation, and the introduction of non-native species, have worsened the environmental damage, which is alarming since many residents and villages along the middle Tocantins River rely on it for water supply, recreation, and fishing. This study assessed the concentration of potentially toxic and essential elements in water samples from four sampling sites distributed along the middle Tocantins River. The monitoring occurred throughout 2023, involving the measurement of parameters both on-site and in the laboratory. Water quality and its health implications were evaluated using the Weighted Arithmetic Water Quality Index (WAWQI), the Water Quality Index (WQI), and the health risk assessment index. The levels of aluminum, copper, iron, magnesium, and selenium exceeded legal standards. Seasonal fluctuations indicate a complex dynamic influenced by climatic or seasonal factors, with February showing the highest values. Site P1, located in urban areas, exhibited elevated mean concentrations for conductivity, total dissolved solids (TDS), and chlorophyll, indicating the need for continuous monitoring. The nitrogen concentrations at P1 raise concerns regarding drinking water quality, which is a concern for the region’s residents who use untreated river water. Despite seasonal variations in element concentrations, the overall WAWQI categorized all sections as “Excellent,” and the WQI rated as “Good.” Human health risk assessments detected no risks, but continuous monitoring and interventions are crucial for sustained water quality improvement.