A soil response framework for use in fatigue assessment of offshore wells and piles is presented. The framework covers clay and sand soil types. It was developed through comprehensive series of physical testing and numerical simulations. It hinges on determination of the unload-reload secant stiffness response of soils degraded under cyclic fatigue loading and reaching a steady-state condition. The framework comprises two calibrated approaches: spring-only and spring-dashpot. The latter is more appropriate when dynamic response of a structure needs to be more accurately determined through for time-domain analysis. Efficacy and validation of the framework are demonstrated through three (3) field monitoring programs involving offshore wells installed in ground conditions ranging from soft clays typically encountered in deepwater to layered sands and clays in shallow waters. Further validation is provided by presenting results from an extensive laboratory testing program involving nine (9) soil samples taken from various geographical locations against the key relationships of the framework. The laboratory tests were conducted in a novel apparatus developed specifically for obtaining soil resistance–displacement relationship for input to fatigue analysis.