This paper evaluates the effectiveness of sustainable agricultural management solutions at a farm level to mitigate water security threats in one of Brazil's agricultural frontiers – the Grande River basin. The paper addresses future challenges to water security in the river basin and explores how effective solutions are at a farm level to mitigate current and future water security threats at a basin scale. Based on the assessment of multiple drivers, higher future water security threats in the region are predicted in 2040 due to climate change, land use modification and corresponding changes in water use. The paper finds that the Formosa do Rio Preto region, which is not currently water-insecure, may turn into a water security hotspot area by 2040. The effective response index for water security (ERI-WS), based on the qualitative assessment of the impact at the farm scale, is used to evaluate the effectiveness of current sustainable management practices in addressing water security challenges. The water security dimensions approach of the ERI-WS shows that >50 % of the sites have technologies that can have positive impacts on the “Drinking water and human well-being”, “Economic activities and development”, “Ecosystem” and the “Resilience” dimensions. The paper finds that 66 % of the farms have efficient soil, land, and water management solutions (ERI-WS > 0.5) to address current and future water security issues. These solutions range from sustainable grazing land management to integrated plant nutrition management to enhanced soil productivity. However, 15 % of the farms located in vulnerable areas of the municipalities of São Desidério, Barreiras and Catolândia have lower effectiveness. Results also indicate that 36 % of the sites, distributed in 8 municipalities, employ nature-based solutions to mitigate water security threats, mainly those related to water quality conditions in downstream areas, indicating the relevance of these practices in the region.