Saline water irrigation is widely used to alleviate water shortage in arid regions. The Taklimakan Desert Highway Shelterbelt (TDHS) has been drip-irrigated long-term using high saline groundwater. However, the effects of saline irrigation on the spatiotemporal dynamics of soil CO2 flux along the TDHS and its underlying mechanisms remain unclear. In this study, we systematically monitored soil CO2 flux along the TDHS and explored its underlying mechanisms under saline drip irrigation with varying salinity levels over two years. The results demonstrated that high-salinity irrigation significantly reduces soil CO2 flux, exhibiting a distinct spatiotemporal variation pattern characterized by a diurnal single-peak curve peaking around 18:00. Within the same irrigation cycle, soil CO2 flux gradually declined over time. Seasonally, soil CO2 flux was significantly higher in summer than in spring or autumn. Spatially, soil CO2 flux in the inter-canopy zone (Z1) was lower than in the undercanopy zone (Z2). These variations were mainly attributed to the effects of irrigation water salinity and sampling location on soil carbon pools, enzyme activity, and soil physicochemical properties. Thus, we conclude that high saline drip irrigation significantly restrains soil CO2 flux through changing soil physicochemical and biological properties. This study provides a scientific basis for accurately assessing the soil carbon sink function of artificial desert shelterbelts in extreme arid areas, while establishing a theoretical foundation for sustainable management and utilization of desert shelterbelts.