The Palatine Hill is among the main archaeological sites of Roman antiquity. Today, this place requires continuous care for its safeguarding and conservation. Among the main problems, slope instabilities threaten the southwestern border of the hill flanked by the Velabrum Valley, as also testified by historical documents. The upper part of the investigated slope is characterized by Middle Pleistocene red-brownish tuffs known as “Tufo Lionato”. The rock mass is affected by two jointing belts featuring the slope edge and its internal portion with different joint frequency and distribution. The analysis of the geometric relationship between the joint systems and the slope attitude evidenced possible planar sliding and toppling failure mechanisms on the exposed tuff cliffs. Potential rock block failures threatening the local cultural heritage were contrasted with preliminary works for site remediation. In addition, stress-strain numerical modelling verified the hypothesis of a tensile origin for the jointing belts, suggested by fracture characteristics and orientation. A first modelling was limited to the southwestern edge of the Palatine Hill and analysed the present stress-strain condition of the slope, proving the inconsistency with the observed deformation. A second modelling was extended to the Palatine-Velabrum slope-to-valley system to consider the role played by the geomorphological evolution of the area on the local slope dynamics during the late Pleistocene-Holocene. Results demonstrate how original conditions of slope instability, deformation and retreat along the Palatine western edge were determined by deep valley incision, and controlled by deformability contrasts within the slope. Slope instability influenced the site occupation and development during the Roman civilization, as also indicated by the remnants of retaining walls of different ages at the slope base.