The concept of the Unified Scaling Law for Earthquakes (USLE), which generalizes the Gutenberg-Richter relationship making use of the fractal distribution of earthquake sources in a seismic region, is applied to seismicity in the Friuli-Venezia Giulia region, FVG (Northeastern Italy) and its surroundings. In particular, the temporal variations of USLE coefficients are investigated, with the aim to get new insights in the evolving dynamics of seismicity within different tectonic domains of FVG. To this purpose, we consider all magnitude 2.0 or larger earthquakes that occurred in 1995–2019, as reported in the catalog compiled at the National Institute of Oceanography and Applied Geophysics (OGS catalog), within the territory of its homogeneous completeness. The observed variability of seismic dynamics for three sub-regions of the territory under investigation, delimited based on main geological and tectonic features, is characterized in terms of several moving averages, including: the inter-event time, τ; the cumulative Benioff strain release, Ʃ; the USLE coefficients estimated for moving six-years time intervals, and the USLE control parameter, η. We found that: 1) the USLE coefficients in FVG region are time-dependent and show up correlated; 2) the dynamical changes of τ, Ʃ, and η in the three sub-regions highlight a number of different seismic regimes; 3) seismic dynamics, prior and after the occurrence of the 1998 and 2004 Kobarid (Slovenia) strong main shocks, is characterized by different parameters in the related sub-region. The results obtained for the FVG region confirm similar analysis performed on a global scale, in advance and after the largest earthquakes worldwide. Moreover, our analysis highlights the spatially heterogeneous and non-stationary features of seismicity in the investigated territory, thus suggesting the opportunity of resorting to time-dependent estimates for improving local seismic hazard assessment. The applied methods and obtained parameters provide quantitative basis for developing suitable models and forecasting tools, toward a better characterization of future seismic hazard in the region.