Extreme streamflow nonstationarity has probably attracted more attention than mean streamflow nonstationarity in the assessment of the impacts of climate change on the water cycle. Nonetheless, a significant decrease in mean streamflow could lead to conditions of scarcity of freshwater in the long-term period, seriously compromising the sustainability of the demand for civil, agricultural, and industrial uses. Regional analyses are useful to better characterize an area’s nonstationarity, since a clear trend at a global scale has not been detected yet. In this article, long-term and high-quality series of streamflow discharges observed in five rivers in the Central Italian Alps, including two multicentury series and two new precipitation and streamflow series not analyzed before, are investigated to statistically characterize individual trends of mean annual runoff volumes. Nonparametric pooled statistics are also introduced to assess the regional trend. Additional climatic and nonclimatic factors, namely, precipitation trends and land cover transformations, have also been considered as potential change drivers. Unlike precipitation, runoff volumes show a marked and statistically significant decrease of −1.45 mm/year, which appears to be homogeneous in the region. The land cover transformation analysis presented here revealed extensive woodland expansions of 510 km2 in 2018 out of the 2650 km2 area measured in 1954, representing 38% of the area investigated in this study: this anthropic driver of enhanced hydrologic losses can be recognized as an additional likely cause for the regional runoff volume decrease.