During shield tunnel construction, karst development along the tunnel axis and in the surrounding area frequently poses a significant threat to engineering safety. To address this challenge, this study proposes multiple grouting systems and systematically analyzes the key mechanical properties of five grout formulations through orthogonal experiments, identifying the optimal formulations for engineering applications. A predictive model was established using linear regression, and its accuracy was validated through independent single-factor experiments. The results indicate the following: (1) Water content is the primary factor influencing fluidity, with its significance varying by system composition. The lake mud-cement grout exhibits the highest compressive pstrength. Moderate sand addition enhances strength, but excessive amounts significantly reduce fluidity. Additives demonstrate system dependency: HY-4 effectively improves fluidity, while sodium silicate significantly increases strength but reduces fluidity. (2) The developed model demonstrates good goodness of fit, with coefficients of determination (R²) ranging from 0.74 to 0.95, without significant autocorrelation or multicollinearity. Validation experiments confirm the model’s high predictive accuracy, with overall trends consistent with the measured data. (3) The lake mud-cement grout (A3B1C3) is recommended for reinforcement projects prioritizing stability, achieving a 28-day compressive strength of 4.74 MPa. The on-site wet clay-cement grout (A2B3C1) is suitable for high-permeability formations, with a strength of 1.1 MPa and a fluidity of 292.5 mm, both exceeding standard requirements. The findings provide optimized formulations and theoretical references for grouting reinforcement in karst tunnel projects.