Degradation of inshore coral reefs due to poor water quality is a major issue, yet it has proved difficult to demonstrate this linkage at other than local scales. This study modeled the relationships between large-scale data on water clarity and chlorophyll and four measures of reef status along the whole Great Barrier Reef, Australia (GBR; 12–24° S). Four biotic groups with different trophic requirements, namely, the cover of macroalgae and the taxonomic richness of hard corals and phototrophic and heterotrophic octocorals, were predicted from water quality and spatial location. Water clarity and chlorophyll showed strong spatial patterns, with water clarity increasing more than threefold from inshore to offshore waters and chlorophyll decreasing approximately twofold from inshore to offshore and approximately twofold from south to north. Richness of hard corals and phototrophic octocorals declined with increasing turbidity and chlorophyll, whereas macroalgae and the richness of heterotrophic octocorals increased. Macroalgal cover experienced the largest water quality effects, increasing fivefold with decreasing water clarity and 1.4-fold with increasing chlorophyll. For each of the four biota, ∼45% of variation was predictable, with water quality effects accounting for 18–46% of that variation and spatial effects accounting for the remainder. Effects were consistent with the trophic requirements of the biota, suggesting that both macroalgal cover and coral biodiversity are partially controlled by energy supply limitation. Throughout the GBR, mean annual values of >10 m Secchi disk depth (a measure of water clarity) and <0.45 g/L chlorophyll were associated with low macroalgal cover and high coral richness, indicating these values to be potentially useful water quality guidelines. The models predict that on the 22.8% of GBR reefs where guideline values are currently exceeded, water quality improvement, e.g., by minimizing agricultural runoff, should reduce macroalgal cover on average by 39% and increase the richness of hard corals and phototrophic octocorals on average by 16% and 33%, respectively (all else being equal). Such guidelines may help focus efforts to implement effective pollution reduction and integrated coastal management policies for the GBR and other Indo-Pacific coral reefs.