The structural evolution and stratigraphic architecture of the Southern Lufeng Depression in the Pearl River Mouth Basin, South China Sea show two second-order sequences (SSQ1 and SSQ2) and nine third-order sequences (WSQ1-5 and ESQ1-4) within the Eocene rift-related successions. Based on integrated interpretations of seismic reflections, well logs and core data, five distinct tectono-stratigraphic patterns are identified: (1) the initial synrift-I sequence (WSQ1) of low tectonic subsidence, overfilled by alluvial fan or fan-delta deposits and volcanic deposits, with no clear systems tracts; (2) the climax synrift-I sequences (WSQ2–4) developed in response to rapid tectonic subsidence, generally consisting of a low-stand systems tract (LST), transgressive systems tract (TST) and high-stand systems tract (HST); (3) the late synrift-I sequence (WSQ5) characterised by a decreased tectonic subsidence rate, dominated by braided delta, deep and shallow lacustrine sediments, mainly constructed by TST and HST; (4) the early synrift-II sequences (ESQ1–2) rapidly filled by braided deltaic sandstone and mainly composed of TST and HST with less common LST units; and (5) the late synrift-II sequences (ESQ3–4), which are totally filled by braided deltaic system in a shallow-water lake setting, presenting typical imbricate clinoforms or sub-parallel seismic configurations, consisting of only TST and HST components. During the climax stage of synrift-I development, the depositional setting changed from a prominent shallow lake (WSQ2) to a deep-lucustrine with turbiditic deposits (WSQ3) and finally dominated by mostly braided deltaic-shallow lacustrine deposits (WSQ4); the HST occupies an increasing proportion from early to late. Furthermore, the stratigraphic patterns, especially LST units of the climax synrift-I stage, are significantly influenced by topographic variations and slope-break belt types in the hanging dip-slope. This study reveals that the spatial and temporal evolution of lacustrine depositional and stratigraphic patterns were significantly controlled by the interplay of tectonic subsidence and sediment supply, and provides a fundamental basis for predicting the favourable reservoirs and geometry of source rocks related to the general variability of Eocene rift-related tectonic subsidence in the Southern Lufeng Depression of the Pearl River Mouth Basin. Furthermore, the topographic responses of differential active fault-stepped patterns associated with magma intrusions, highlight the variability of relevant sequence architectures in the hanging dip-slope in lacustrine rift basins.