Pakistan is amongst the most water-stressed countries in the world, with changes in the frequency of extreme events, notably droughts, under climate change expected to further increase water scarcity. This study examines the impacts of climate change and anthropogenic activities on the runoff of the Kunhar River Basin (KRB) in Pakistan. The Mann Kendall (MK) test detected statistically significant increasing trends in both precipitation and evapotranspiration during the period 1971–2010 over the basin, but with the lack of a statistically significant trend in runoff over the same time-period. Then, a change-point analysis identified changes in the temporal behavior of the annual runoff time series in 1996. Hence, the time series was divided into two time periods, i.e., prior to and after that change: 1971–1996 and 1997–2010, respectively. For the time-period prior to the change point, the analysis revealed a statistically significant increasing trend in precipitation, which is also reflected in the runoff time series, and a decreasing trend in evapotranspiration, albeit lacking statistical significance, was observed. After 1996, however, increasing trends in precipitation and runoff were detected, but the former lacked statistical significance, while no trend in evapotranspiration was noted. Through a hydrological modelling approach reconstructing the natural runoff of the KRB, a 16.1 m3/s (or 15.3%) reduction in the mean flow in the KRB was simulated for the period 1997–2010 in comparison to the period 1971–1996. The trend analyses and modeling study suggest the importance of anthropogenic activities on the variability of runoff over KRB since 1996. The changes in streamflow caused by irrigation, urbanization, and recreational activities, in addition to climate change, have influenced the regional water resources, and there is consequently an urgent need to adapt existing practices for the water requirements of the domestic, agricultural and energy sector to continue being met in the future.