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Summary 1. Planning for the conservation of river biodiversity must involve a wide range of management options and account for the complication that the effects of many actions are spatially removed from these actions. Reserve design algorithms widely used in conservation planning today are not well equipped to address such complexities. 2. We used process‐based models to estimate the expected persistence of river biodiversity under alternative catchment‐wide management scenarios and applied it in the Hunter Region (37 000 km²) in southeastern Australia. 3. The biological condition of 12 197 subcatchments was estimated using a multiple linear regression model that related assessments of the integrity of macroinvertebrate assemblages to human‐induced disturbances at river sites. The best‐fit model ( R 2 = 0.76) used measures of both local and catchment‐wide disturbances as well as elevation and distance from source as predictor variables. Based on the outputs of this model, we estimated that substantial loss of river biodiversity had occurred in some parts of the coastal fringes and the lower parts of the larger river systems. The most affected river type was small, low‐gradient streams. 4. The predicted biodiversity condition together with river types based on macroinvertebrate assemblages and abiotic attributes was used to estimate a biodiversity persistence index (BDI). 5. A priority value for each subcatchment was calculated for different actions by changing the disturbance values for that subcatchment and calculating the resulting marginal change in regional BDI. Maps were thereby created for three different types of priority: catchment protection priority, catchment restoration priority and river section conservation priority. 6. The subcatchments of high catchment protection priority for river biodiversity were mostly in the uplands and within protected areas. The river sections of high conservation priority included many coastal lowland rivers in and around protected areas as well as many upland headwater streams. Subcatchments of high priority for catchment restoration were mostly in coastal areas or lowland floodplains. 7. This approach may be particularly well suited to guide the integrated implementation of three place‐based protection strategies proposed for freshwaters: focal areas, critical management zones and catchment management zones.