Integrated water resources management (IWRM) has been central to water governance and management worldwide since the 1990s. Recognizing the significance of an integrated approach to water management as a way to achieve the Sustainable Development Goals (SDGs), IWRM was formally incorporated as part of the SDG global indicator framework, thus committing the UN and its Member States to achieving high IWRM implementation by 2030 and measuring progress through SDG indicator 6.5.1. This paper examines the extent to which the implementation of IWRM improves the sustainable management of water and the health of water-related ecosystems—a first-of-its-kind in terms of quantitative analysis on a global scale. To achieve this objective, we conducted regression analyses between SDG 6.5.1 (both IWRM (total score) and the dimensions of SDG 6.5.1) and key water-related environmental sustainability indicators: SDG 6.2.1a (access to basic sanitation), 6.3.1 (treated wastewater), 6.4.1 (water-use efficiency), 6.4.2 (water stress), 6.6.1 (freshwater ecosystems, although here the trophic state and turbidity variables were used) and 6.3.2 (ambient water quality). Our analysis covers 124 countries for all these SDGs, with the exception of SDG 6.3.1 and SDG 6.3.2, which cover 112 and 85 countries, respectively. Results show that IWRM—to different degrees—is mainly associated with the good status of water-related sustainability indicators, with the exception of water stress, water quality, and turbidity. We observe a strong impact of control variables such as governance arrangements, economic situation and environmental and geographical conditions. Lagged effects and the scope of the framework may also explain some observed variations in the degree of association. Our study highlights the importance of further uncovering the interlinkages between IWRM implementation and the achievement of water-related environmental sustainability. Overall, the results suggest that although IWRM implementation is primarily linked to sustainable water management and the health of water systems, context-specific factors should be taken into account when evaluating its effectiveness, to enable policy- and decision-makers to make the necessary adjustments to optimize its outcomes.