Floodplains are habitats with an outstanding biodiversity but have been strongly affected by anthropogenic activities such as channelization and bank enforcement. The remaining floodplains are impacted by climate change-driven alterations in the hydrological regime and by chemical stressors. However, the extent and interactive effects of these stressors are not well understood, especially in small-scale floodplains. In a mesocosm experiment, we therefore studied aquatic and riparian (floodplain) invertebrate communities in response to changes in the hydrological regime as predicted by climate change and the application of the biocide Bacillus thuringiensis israelensis (Bti). The mesocosm facility contained 12 separated floodplain mesocosms. The control hydrological regime consisted of a 40-cm water level and one monthly flood throughout the year, while the altered hydrological regime (scenario) had weekly floods during winter and a lower water level during summer. In addition, half of both the control and scenario floodplain mesocosms were treated with Bti at the maximum field rate applied for mosquito control. We found that the hydrological regime had contrasting effects for the aquatic and riparian communities. While the number of individuals of most aquatic invertebrates decreased in the scenario floodplain mesocosms, we found predominantly higher number of individuals of riparian arthropods. Furthermore, Bti had negative effects on some nontarget organisms, such as ground beetles and mayflies, and interacted with the hydrological regime in some cases. We conclude that the effects of both hydrological regime and Bti are taxa-dependent and that the hydrological regime revealed opposing effects between aquatic and riparian habitats.