In aquatic ecosystems, excessive nutrient loading is a global problem that can induce regime shifts from macrophyte- to phytoplankton-dominated states with severe consequences for ecosystem functions. Most agricultural landscapes are sites of nutrient and pesticide loading, which can interact with other stressors (e.g., warming) in additive, antagonistic, synergistic or reversed forms. The effects of multiple stressors on the resilience of macrophyte-dominated states and on critical thresholds for regime shifts are, however, unknown. We test the effects of individual and combined stressors of warming, nitrate, and various pesticides typically found in agricultural run-off (ARO) on the growth of macrophytes, periphyton, and phytoplankton in microcosms. We applied a one-level replicated design to test whether ARO induces a regime shift and a multifactorial dose–response design to model stressor thresholds and disentangle stressor interactions along a gradient. The individual stressors did not induce a regime shift, but the full ARO did. Nitrate and pesticides acted synergistically, inducing a shift with increasing phytoplankton biomass and decreasing macrophyte biomass. Warming amplified this effect and lowered critical thresholds for regime shifts. Shallow aquatic ecosystems in agricultural landscapes affected by global warming thus increasingly risk shifting to a turbid, phytoplankton-dominated state, and negatively impacting ecosystem service provisioning. Multiple stressor interactions must be considered when defining safe operating spaces for aquatic systems.