A new prediction model is derived for the uplift capacity of suction caissons using a hybrid method coupling genetic programming (GP) and simulated annealing (SA), called GP/SA. The predictor variables included in the analysis are the aspect ratio of caisson, shear strength of clayey soil, load point of application, load inclination angle, soil permeability, and loading rate. The proposed model is developed based on well established and widely dispersed experimental results gathered from the literature. To verify the applicability of the proposed model, it is employed to estimate the uplift capacity of parts of the test results that are not included in the modeling process. Traditional GP and multiple regression analyses are performed to benchmark the derived model. The external validation of the GP/SA and GP models was further verified using several statistical criteria recommended by researchers. Contributions of the parameters affecting the uplift capacity are evaluated through a sensitivity analysis. A subsequent parametric analysis is carried out and the obtained trends are confirmed with some previous studies. Based on the results, the GP/SA-based solution is effectively capable of estimating the horizontal, vertical and inclined uplift capacity of suction caissons. Furthermore, the GP/SA model provides a better prediction performance than the GP, regression and different models found in the literature. The proposed simplified formulation can reliably be employed for the pre-design of suction caissons. It may be also used as a quick check on solutions developed by more time consuming and in-depth deterministic analyses.