Lowland streams are inherently exposed to multiple stressors such as nitrate and pesticides from neighbouring agricultural areas and warming due to ongoing climate change. Determining how multiple different stressors may interact in affecting complex ecosystems remains a challenge. Our study aimed to investigate the effect of multiple stressors, combining warming and exposure to agricultural run-off (ARO), on small streams and to determine how biotic interactions will mediate the response of these aquatic ecosystems. Our hypothesis was that warming will amplify the negative effect of ARO. We used 16 outdoor flume mesocosms to simulate lowland streams. At the beginning of the experiment, each mesocosm was prepared with macrophytes planted in sandy sediments, a natural inoculum of periphyton and phytoplankton, the grazer Lymnaea stagnalis, the shredder Gammarus roeseli, the filter feeder Dreissena polymorpha and leaf litter. We tested in a factorial design the effect of heating (3 °C above ambient temperature) and a cocktail of pesticides and nitrate to simulate ARO during 8 weeks between April and June 2021. Phytoplankton density remained low during the first six weeks of the experiments in all treatments before increasing strongly in ARO-containing mesocosms. All the mesocosms got rapidly covered by mats of filamentous algae, with a significantly higher coverage in the ARO treatment. Filamentous algae coverage decreased more rapidly in the heated treatments. The macrophyte community was dominated by Potamogeton perfoliatus in all the mesocosms; its growth was negatively affected by ARO but positively by warming. Periphyton achieved a higher biomass in ARO-treated mesocosms but the differences between the treatments diminished strongly during the three last weeks of the experiment. The invertebrates (L. stagnalis, G. roeseli, D. polymorpha) were all negatively affected by ARO. Warming favoured L. stagnalis reproduction and the breakdown of leaf litter. Exposure to the different stressors led to complex responses of the ecosystem. The direct effects of ARO and warming on grazers, periphyton and filamentous algae were likely at the origin of an indirect effect on the macrophytes through shading and nutrient competition. Overall, our results did not indicate an enhanced effect of ARO on the ecosystems when streams get warmer.