The dynamics of nutrients, phytoplankton, zooplankton and water clarity of the iconic Great Barrier Reef World Heritage Area (GBRWHA) are influenced by seasonal variation in coastal and oceanic conditions, and anthropogenic inputs. We use the 3-dimensional coupled catchment-hydrodynamic-sediment-wave-optical-biogeochemical eReefs model to hindcast nutrient and planktonic responses to changes in seasonal and annual variability over a six-year period (2011–2016). In this paper we present a comparison of the eReefs model conducted against a range of in situ observations that included 24 water quality moorings, 2 nutrient sampling programs (with a total of 18 stations) and time-series of taxon-specific plankton abundance. At 14 near-coastal stations the simulated chlorophyll a (Chl a), when compared with chlorophyll extractions from water samples, had an average root mean square (RMS) error of 0.30 mg m−3 and a Willmott index of 0.59. For the same sites, simulated turbidity, when compared with turbidity sensors, had a Willmott index of 0.58 and simulated nitrate + nitrite had a Willmott index of 0.41 when compared with tri-annual water samples. Comparison with a spatially-resolved statistical model of zooplankton based on textgreater 900 observations in the region showed similarities in the relationship and spatial distribution of simulated and observed biomass, where both show zooplankton biomass is greatest inshore, biomass is highest around shallow reef areas and in the southern and central GBRWHA, and greater in summer than winter. Additionally, we investigate planktonic and nutrient responses to climatic variation. The first two years of the simulation coincided with La Niña events that drive greater than average winds, rainfall and river discharge. Throughout all years, simulated Chl a increases from north to south and from outer to inner coastal regions. Dissolved inorganic nitrogen, primary production and phytoplankton biomass were higher during La Niña in inshore and mid-shelf waters, while offshore regions were similar in all years from 2011 to 2016. Simulated Secchi depth was deeper offshore and decreased from offshore to inner coastal regions and from north to south. The eReefs simulation contributes to the understanding at a high spatial and temporal resolution of where and how nutrients and plankton originate and interact within the Great Barrier Reef.