The increasing accuracy and spatiotemporal resolution of space geodetic techniques have positively impacted the study of shallow crustal deformation in response to the redistribution of water masses. Measurable deformations have been documented in areas where snow and water variability is large and persists over sufficiently long periods. Here we analyze GPS time series and hydrological data from the Central-Southern Apennines, a tectonically-active region hosting large karst aquifers. We document the occurrence of regional-scale horizontal and vertical transient deformation that is clearly correlated to seasonal and multiyear hydrological variability. These transient signals, which are most strongly observed at GPS sites surrounding the main karst aquifers, modulate long term tectonic deformation. Our results suggest that the karst aquifers in this region experience alternating periods of expansion and contraction in response to increasing/decreasing precipitation and, consequently, higher/lower hydraulic head in the aquifers. Thanks to the availability of a dense continuous GPS network and complementary hydrological datasets, we are able to verify the processes causing the observed deformation. We model the shallow crust in the region as a continuous anelastic solid and use Green's functions for finite strain cuboid sources to estimate the strain rate distribution associated with the GPS observations. We use the Mw 6.1 L'Aquila earthquake, which struck the Central Apennines in 2009 and whose effects are evident in geodetic data, to document the potential effects of moderate earthquakes on karst aquifers and to demonstrate the importance of correctly discerning tectonic from nontectonic signals in geodetic time series. Enhanced understanding of the karst aquifers behavior is of primary interest for improved management of this vital water resource and for a better understanding of the possible interactions between groundwater content and pore pressure variations in the crust and seismicity.