The world's freshwater molluscan fauna is facing unprecedented threats from habitat loss and degradation. Declines in native populations are mostly attributed to the human impact, which results in reduced water quality. The objectives of our survey were to analyse the structure of the mollusc communities in a medium‐sized lowland river and to determine the most important environmental variables at different spatial scales, including landscape structure, catchment land use and instream environmental factors that influence their structure. Our survey showed that a medium‐sized river, that flows through areas included in the European Ecological Natura 2000 Network Programme of protected sites, provides diverse instream habitats and niches that support 47 mollusc species including Unio crassus, a bivalve of Community interest, whose conservation requires the designation of a special conservation area under the Habitats Directive Natura 2000. This survey showed that mollusc communities are impacted by several environmental variables that act together at multiple scales. The landscape structure within buffer zones, catchment land use and instream environmental variables were all important and influenced the structure of mollusc communities. Therefore, they should all be taken into consideration in the future restoration of the river, future management projects and programmes for the conservation of biodiversity in running waters. The results of this study may be directly applicable for the rehabilitation of river ecosystems and are recommended to stakeholders in their future decision concerning landscape planning, monitoring species and their habitats, conservation plans and management in accordance with the requirements of sustainable development.