Assessing habitat selection is essential to protecting threatened species but also to understand what factors influence species that, although globally not currently in decline, act as flagships of their ecosystems and remain highly vulnerable to human impacts, such as the Eurasian otter. This paper examines otter habitat selection at the river reach scale in two heavily anthropized river basins. Both river basins encompass a wide spectrum of human pressures and biogeographic units, which offers an excellent opportunity to assess otter responses to anthropogenic activities in different scenarios. Through two modelling approaches (structure-agnostic way and a priori hypothesized habitat factors) we demonstrate that otters currently inhabiting these human-dominated landscapes show a trade-off between a preference for highly productive areas and for well-structured and safe areas. We suggest that habitat simplification and human disturbance, which were of minor relevance to the dramatic decline of otter populations in the 20th century, are emerging as potential threats in the context of worldwide increasing land use intensification. Furthermore, we found that otter habitat requirements were remarkably more stringent for breeding site selection than for occurrence, particularly concerning variables related to human disturbance. The results of this work provide tools for integrating ecological criteria oriented to effective otter conservation into river management in human-dominated landscapes, as well as serving as methodological support for lowland river restorations. Our results suggest that long-term otter conservation in anthropized rivers will depend on ensuring the availability of habitat patches that maintain sufficient structural complexity away from intensely outdoor recreational activities.