The settlement behavior of composite foundations plays an important role in the serviceability and stability of the subgrade or other infrastructures supporting the foundation. However, in water-rich flood plains, due to the complexity of the soft soil properties, the settlement behavior has not been well understood. The objective of this study is to investigate the effects of various key factors on the settlement behavior of composite foundations with deep mixed piles supporting highway subgrade in water-rich flood plains. The investigated subgrade is in operation, and the vehicle load is taken into account. The G347AH Project is considered in this study. Several typical models for predicting composite foundation settlements are discussed. By performing three-dimensional finite difference analysis, a comparison is made between the settlement behavior of the natural foundation and the composite foundation with deep mixed piles. Based on the single factor sensitivity analysis and the multi-factor orthogonal experimental design, the effects of pile length, pile diameter, pile spacing, pile elasticity modulus, cushion elasticity modulus, and cushion thickness on the composite foundation settlement are captured. It is found that among these factors, the degree of influence of pile length is superior. The composite foundation settlements predicted by the models agree well with the field-monitoring data, with the error being about 8.42% and 6.38%, respectively, at two monitoring sections. The research conducted in this paper can effectively reduce the probability of various settlement-related disasters occurring on highway subgrades in water-rich flood plains. Moreover, the research has important theoretical guidance for design optimization in terms of settlement control of highway subgrades in soft soil areas.