Upscaling of ecological effects from indoor microcosms to outdoor mesocosms bridging the gap between controlled laboratory conditions and highly complex natural environments poses several challenges: typical standard water types used in laboratory experiments are not feasible in large outdoor experiments. Additionally, moving from the micro- to meso-scale, biodiversity is enhanced. We performed an indoor microcosm experiment to determine the effects of agricultural run-off (ARO) on a defined benthic–pelagic community comprising primary producers and primary consumers, exposed to ambient summer temperature and +3.5 °C. Treatments were replicated in two water types (standard Volvic and Munich well water). We then scaled up to outdoor mesocosms using an ARO concentration gradient and +3 °C warming above ambient temperature, using Munich well water. We included the same benthic macroorganisms but more complex periphyton and plankton communities. All the functional groups were affected by stressors in the microcosms, and a shift from macrophyte to phytoplankton dominance was observed. While effects were present, they were less pronounced in the mesocosms, where a higher biodiversity may have modified the responses of the system to the stressors. The stressor effects observed in controlled experiments may thus be masked in more complex outdoor experiments, but should not be interpreted as “no effects”.