Pesticide concentrations are correlated with regional declines in stream invertebrate diversity. Experimental studies have identified that pesticides can have strong and persistent negative effects on aquatic ecosystems. These effects may occur at concentrations orders of magnitude lower than laboratory toxicity studies predict. Synergism among stressors is one explanation for observed laboratory–field differences. However, the true effect of pesticides on stream invertebrates remains uncertain, given interactions between stressors and natural environmental conditions. We experimentally examined multiple-stressor effects on stream invertebrate assemblages and leaf litter breakdown using 24 independent ~900 L re-circulating outdoor mesocosms in a semi-orthogonal design. Two pulses of the pesticide malathion (C10H19O6PS2) were delivered at low and high concentrations (Pulse 1: low at 0.1 and high at 1 µg/L; Pulse 2: at 2.5 and 25 µg/L). These were crossed with a treatment combining stressors commonly associated with agricultural development; nitrogen, phosphorus and sediment (kaolinite). Malathion degradation was rapid (<24 hr half-life) in all treatments, likely because of photolysis, hydrolysis, the presence of biofilms and sorptive processes. There were significant differences in invertebrate assemblages between treatments, where malathion contributed to 48% and 87% of deviance during Pulse 1 and 2 respectively. Malathion had strong negative effects during Pulse 2, with declines occurring between control and high pesticide treatments in Ephemeroptera, Plecoptera and Trichoptera abundances (Cohen's d = 3.08), invertebrate richness (d = 3.57) and total abundance (d = 3.31). Despite the dominant effects of malathion on invertebrates, agricultural stressors inhibited rates of leaf litter breakdown (p < 0.05), and weakly mitigated malathion toxicity in mesocosms (e.g. PERMANOVA, P ≈ 0.1). Malathion breakdown analysis indicated sediment addition reduced malathion concentrations through alkaline hydrolysis and sorption. Experimental assays on common taxa supported sediment-malathion interactions resulted in antagonism. Synthesis and applications. Pesticide effects were not synergistic with the stressors tested here. Indeed, sensitivity-dependent stressor antagonisms were observed, reinforcing a mechanistic understanding of stressor effects and interactions is important. Among aquatic stressors examined, malathion had dominant effects on invertebrate assemblages, despite rapid degradation. Our results suggest that pesticide effects may be underestimated within ecosystems, where pesticides can have severe community-wide effects, but rapid pesticide breakdown and sorptive processes may conceal causal links.