The design of foundations supporting offshore structures and subjected to excessive cyclic loading episodes become challenged when embedded in soft marine clays. A deterioration in the undrained shear strength of marine clays with the generation of excess pore water pressure under cyclic loading significantly affects the offshore infrastructure’s stability. It leads to large lateral deformations that might be failing both superstructure and infrastructural systems. Monopiles are extensively used in supporting offshore structures due to their high resistance to extensive lateral cyclic loading. The response of the Monopile-Clay system to lateral cyclic loading drew the attention of researchers over the years; they conducted experimental, field, and numerical studies to examine the suitability of the methods adopted in the design codes, which is still a controversial issue. This research aims to study the cyclic performance of marine clays and the monopile-clay system and measure the marine clay fatigue life and how it interferes with the system’s failure. A parametric sensitivity analysis using the Artificial Intelligence technique was proposed to highlight the complicated behavior of marine clays and to allocate the clay parameter(s) that primarily affect its behavior when subjected to cyclic loading. Datasets collected from the literature were used to measure the threshold cyclic stress ratio (CSR) for a wide range of marine clays worldwide. Moreover, a modified safe zone concept was proposed to predict the clay’s response, whether it fails or maintains equilibrium. The most significant clay parameters that impact its response were detected, and a predictive ANN model was proposed. The model successfully predicts the marine clay response to cyclic loading. The fatigue life estimation of marine clays was measured by performing a series of strain-controlled tests under different strain amplitudes. Three major turning points in the marine clay’s fatigue life were defined: (1) the crack initiation, (2) the crack propagation fatigue life, and (3) the transition point where the plastic strains become dominant and control the clay’s behavior. Furthermore, a new correlation of the degradation parameter (t) was proposed based on cycling the marine clays until failure. A 2D numerical investigation was performed under the same tested parameters of the strain-controlled tests to measure the monopile-clays system fatigue life. The system was analyzed under displacement-controlled loading amplitude to measure the actual clay’s response and deterioration over the embedded depth of the monopile and by increasing the number of cycling. The detected  P-N profiles can be an efficient tool to develop new design criteria that fulfill the fatigue limit state (FLS) requirements.