In Northern Apennines, upper Lutetian-Bartonian sedimentary mélanges, corresponding to ancient mud-rich submarine mass transport deposits, are widely distributed along the exhumed outer part of the External Ligurian accretionary wedge (ELAW), over an area of ∼300 km long and tens of kilometres wide. The occurrence of CH4-derived carbonate concretions (septarians) in a specific tectono-stratigraphic position below sedimentary mélanges, allows us to document the relationships between a significant period of regional-scale slope failure, climate change (Early and Middle Eocene Optimum stages; EECO and MECO), gas hydrates dissociation, and accretionary tectonics during the Ligurian Tectonic Phase (early-middle Lutetian). The distribution of septarians at the core of thrust-related anticlines documents that gas hydrates dissociation was triggered by accretionary tectonics rather than climate changes. The different ages of slope failure emplacement and septarians formation support that gas hydrates dissociation was not the most important triggering for slope failure. The latter occurred during a tectonic quiescence stage associated with a depositional regressive trend, and probably minor residual tectonic pulses, which followed the Ligurian Tectonic Phase, favoring the dynamic re-equilibrium of the ELAW. Our findings provide useful information for better understanding factors controlling giant slope failure events in modern accretionary settings, where they may cause tsunamis.