Abstract: In the engineering design of ship lifts, determining the effective water depth in the ship chamber directly affects the power demand of the electric drive system and the overall project cost. Currently, the determination of effective water depth in the ship chamber of large domestic ship lifts in China primarily relies on empirical formulas specified in design codes or physical model tests. However, the allowable range of surplus water depth in the standard formula is wide and highly subjective, posing certain difficulties for design work. Physical model tests for ships entering and exiting the ship lift chamber are time-consuming and costly and can only analyze the squat of representative vessel types at a fixed speed. They cannot quantitatively evaluate the safety risks associated with different types of ships entering and exiting the chamber at varying speeds and under varying chamber water depths. Meanwhile, research on the squat of different types of vessels during entry into and exit from the ship chamber, as well as the probability of their safe passage, remains relatively limited. This paper proposes a Monte Carlo simulation-based method for determining the effective water depth of the ship chamber, treating key influencing factors—such as vessel type, navigation speed, and water depth variation—as random variables. By integrating prior research findings on vessel squat characteristics during vessel passage through the chamber, a coupled relationship model is established between vessel squat and influencing factors, including speed, chamber water depth, vessel tonnage, and block coefficient. Based on this model, the Monte Carlo method is utilized to perform random sampling simulations, considering key influencing factors such as vessel type, speed, and water depth variations as random variables. For a given effective water depth of the ship lift chamber, the overall safety probability of different types of ships safely passing through the chamber is calculated. Taking the navigation project at the high dams on the lower Jinsha River, which involves ship lifts for 3,000–8,000-ton vessels, as an example, the Monte Carlo simulation results indicate that, according to the standard of a safety margin of 0.60 m under-keel clearance proposed in the design and scientific research of the Three Gorges ship lift, to ensure the safe passage of a 3,000-ton vessel (with a draft of 3.50 m) through the ship lift, the water depth of the ship lift chamber must be at least 4.60 m; to ensure the safe passage of the predominant 5,000-ton-class vessels (with a draft of 4.30 m), the effective water depth of the ship chamber must be at least 5.40 m. To ensure the safe passage of the largest 8,000-ton-class vessels (with a draft of 5.50 m), the required effective water depth of the ship chamber increases to at least 6.80 m. Based on the standard of a safety margin of 0.80 m under-keel clearance, to ensure the safe passage of 3,000-ton vessels through the ship lift, the water depth of the ship lift chamber must be at least 4.80 m; to ensure the safe passage of 5,000-ton vessels, the water depth of the ship lift chamber must be at least 5.60 m; to ensure the safe passage of the largest 8,000-ton vessels, the required effective water depth of the ship lift chamber must be at least 7.00 m. This method provides a probabilistic design approach based on risk analysis for determining the effective water depth of ship chambers. Compared with the standard calculation formula, this method provides a more economical approach to determining the effective water depth of the ship lift chamber and offers a new theoretical basis and decision-making tools for the optimized design of large-scale ship lifts.