Summary: Pervasive and accelerating changes to ecosystems due to human activities remain major sources of uncertainty in predicting the structure and dynamics of ecological communities. Understanding which biotic interactions within natural multitrophic communities are weakened or augmented by invasions of non-native species in the context of other environmental pressures is needed for effective management. We used multivariate autoregressive models with detailed time-series data from largely freshwater and brackish regions of the upper San Francisco Estuary to assess the topology, direction and strength of trophic interactions following major invasions and establishment of non-native zooplankton in the early 1990s. We simultaneously compared the effects of fish and clam predation, environmental temperature and salinity intrusion using time-series data from >60 monitoring locations spanning more than three decades. We found changes in the networks of biotic interactions in both regions after the major zooplankton invasions. Our results imply an increased pressure on native herbivores; intensified negative interactions between herbivores and omnivores; and stronger bottom-up influence of juvenile copepods but weaker influence of phytoplankton as a resource for higher trophic levels following the invasions. We identified salinity intrusion as a primary pressure but showed relatively stronger importance of biotic interactions for understanding the dynamics of entire communities. Synthesis and applications. Our findings highlight the dynamic nature of biotic interactions and provide evidence of how simultaneous invasions of exotic species may alter interaction networks in diverse natural ecosystems over large spatial and temporal scales. Efforts to restore declining fish stocks may be in vain without fully considering the trophic dynamics that limit the flow of energy to target populations. Focusing on multitrophic interactions that may be threatened by invasions rather than a limited focus on responses of individual species or diversity is likely to yield more effective management strategies.