There is a close relationship between the evolution of the Cambrian–Ordovician paleo-uplifts and their hydrocarbon accumulation in the Southwest Tarim Depression. Using regional 2D seismic data interpretation, the structural morphology of the top of the Ordovician carbonate rocks in the Southwest Tarim Depression at different historical geologic stages is mapped. Combined with analysis of the discovered oil and gas reservoirs, the regularity of the hydrocarbon distribution in the Southwest Tarim Depression is investigated. Research shows that the evolution of the Cambrian-Ordovician paleo-uplifts in the Southwest Tarim Depression can be divided into four stages: (1) formation of the paleo-uplifts, (2) steady subsidence of the eastern paleo-uplift, (3) migration and adjustment of the western paleo-uplift and (4) strong subsidence and extinction of the paleo-uplifts. The Cambrian-Ordovician strata in the Southwest Tarim Depression experienced a seesaw-like structural reconstruction from an early north-dipping slope to a late south-dipping slope. During the structural reconstruction process, a pivot zone was located at the position of the current Maigaiti Slope, proving favorable for hydrocarbon accumulation and preservation. The fault zones in the eastern and western paleo-uplifts of the Maigaiti slope finalized during the Late Hercynian Period were favorable to preserving paleo-oil reservoirs. In contrast, the fault zones in the northern margin of the Maigaiti Slope, where the current tectonic uplift is located, were favorable for the accumulation of gas reservoirs.