We reconstructed the seismotectonic setting of the area comprising the northeastern Friuli Plain and the Julian pre-Alpine border (NE Italy) by integrating geological and seismological data. The study area represents the junction between the SSE-verging polyphase thrust-front of the south-Alpine Chain and the NW–SE-trending strike-slip faults of the eastern Friuli–western Slovenia domain. Following a multidisciplinary approach, the 3D geometry of the Susans–Tricesimo thrust system was reconstructed through the elaboration of four geological cross sections derived from the interpretation of ENI industrial seismic lines. In a second step, the seismogenic volume of the central-eastern Friuli area was investigated through hypocentral distribution analysis: the seismic events of the latest 50 years (1976–1977 and 1978–2019 time intervals) were plotted on four NE-SW-oriented seriated sections together with the fault plane’s geometry. Through this procedure, we were able to investigate the relationship between the NW-SE-striking high-angle faults, which characterize the northern Julian pre-Alps, and the WSW-verging medium-angle reverse fronts located at the piedmont of the Friuli plain, which experienced NW-SE- to NNW-SSE-oriented compression starting at least from the Pliocene. In detail, we examined the involvement of these structures during the seismic sequences of May and September 1976, in terms of activation and/or interaction. The resulting seismotectonic model highlights the interplay between transpressive/strike-slip and reverse planes. In particular, this study suggests that Predjama and Maniaglia transpressive faults strongly control the stress release and likely played a fundamental role both during the 6 May (Mw 6.5) and 15 September (Mw 6.0) Friuli earthquakes.