This study aims to address the question: can the structural reliability of an offshore wind turbine (OWT) under fatigue loading conditions be predicted more consistently? To respond to that question this study addresses the following specific aims: (1) to obtain a systematic approach that takes into consideration the amount of information available for the uncertainty modeling of the model input parameters and (2) to determine the impact of the most sensitive input parameters on the structural reliability of the OWT through a surrogate model. First, a coupled model to determine the fatigue life of the support structure considering the soil-structure interaction under 15 different loading conditions was developed. Second, a sensitivity scheme using two global analyses was developed to consistently establish the most and least important input parameters of the model. Third, systematic uncertainty quantification (UQ) scheme was employed to model the uncertainties of model input parameters based on their available—data-driven and physics-informed—information. Finally, the impact of the proposed UQ framework on the OWT structural reliability was evaluated through the estimation of the probability of failure of the structure based on the fatigue limit state design criterion. The results show high sensitivity for the wind speed and moderate sensitivity for parameters usually considered as deterministic values in design standards. Additionally, it is shown that applying systematic UQ not only produces a more efficient and better approximation of the fatigue life under uncertainty, but also a more accurate estimation of the structural reliability of offshore wind turbine's structure during conceptual design. Consequently, more reliable, and robust estimations of the structural designs for large offshore wind turbines with limited information may be achieved during the early stages of design.