Aquatic ecosystems are exposed to multiple environmental pressures including chemical contamination. Polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) known as preoccupying substances for the environment. Active biomonitoring (ABM) is a surveillance method for polluted aquatic ecosystems measuring bioavailable contamination. In this work, the aim was to quantify the total links between environmental pressures and bioavailable contamination (for PAHs and PCBs) at the French national scale. Based on 245 sites experimented by ABM from 2017 to 2019, environmental pressures (anthropogenic pressures and environmental parameters) were defined (point source landfill density, point source urban density, point source industry density, point source road density, nonpoint source industry density, nonpoint source road density, nonpoint source urban density, nutrients and organic matter, slope, dams, straightness, coarse sediment, summer precipitation, hydrographic network density and watershed size) and characterized by one or a combination of measures called stressor indicators. The links between environmental pressures and bioavailable POPs contamination (ABM measure) at a large spatial scale were defined and quantified via structural equation modeling. Point source urban density, nutrients and organic matter, summer precipitation, straightness and point source industry density are correlated positively with PAH bioavailable contamination. In contrast, nonpoint source urban density, nonpoint source industry density, nonpoint source road density and watershed size are positively correlated with PCB bioavailable contamination. The dominant pressures linked to PAHs and PCBs were different, respectively local and large-scale pressures were linked to PAH bioavailable contamination, and only large-scale pressures were linked to PCB bioavailable contamination.