The scour envelope directly determines the burial depth of large cross-river tunnels. Taking the Chongtai Yangtze River Tunnel as a case study, this paper systematically investigates the key factors influencing the determination of the riverbed scour envelope for large tunnels in estuarine regions. The study demonstrates that defining the scour envelope for large cross-river tunnels in the Yangtze River estuary requires comprehensive consideration of overall river regime conditions, geological conditions, stability of historical scour holes, the evolution-derived (measured) scour envelope, and model-derived scour envelope. Taking into account the recent frequent occurrence of deep scour holes near the alignment of the Chongtai Yangtze River Tunnel, the composite scour envelope is controlled by the deepest point at an elevation of −58.2 m. The results of this research have been successfully applied in engineering design.